US 20140220079A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0220079 A1 ASAR et al. (43) Pub. Date: Aug. 7, 2014

(54) VACCINE COMPOSITION FOR MUCOSAL (30) Foreign Application Priority Data ADMINISTRATION Feb. 5, 2013 (JP) ...... 2013-020909 (71) Applicant: NITTO DENKO CORPORATION, Osaka (JP) Publication Classification (72) Inventors: Daisuke ASARI. Osaka (JP); Arimichi (51) Int. Cl. OKAZAKI, Osaka (JP); Kyohei A 6LX39/39 (2006.01) MATSUSHITA, Osaka (JP); Katsuyuki A6139/00 (2006.01) OKUBO, Osaka (JP); Yoshiki MAEDA, (52) U.S. Cl. Osaka (JP): Takuya SHISHIDO, Osaka CPC ...... A61K 39/39 (2013.01); A61 K39/00II (JP); Wenjing LI, Osaka (JP): (2013.01); A61K 2039/542 (2013.01) Mitsuhiko HORI, Osaka (JP); Haruo USPC ...... 424/277.1 SUGIYAMA, Osaka (JP) (57) ABSTRACT (21) Appl. No.: 14/166,973 The present invention provides a cancer vaccine composition for mucosal administration comprising (i) a HER2/neu E75 and/or a modified HER2/neu E75 peptide; and (ii) a (22) Filed: Jan. 29, 2014 first cellular immunity induction promoter. US 2014/0220079 A1 Aug. 7, 2014

VACCNE COMPOSITION FOR MIUCOSAL sequence as the E75 antigen peptide and the MHC class I ADMINISTRATION molecule; or a tumor cell having a complex of HER2/neu E75 peptide (derived from the endogenous HER2/neu protein) of TECHNICAL FIELD an sequence having cross immunoreactivity with the E75 antigen peptide and the MHC class I molecule, and 0001. The present invention relates to a cancer vaccine for attacks the recognized tumor cells. Therefore, the HER2/neu mucosal administration comprising a HER2 antigen peptide, E75 peptide, and the modified HER2/neu E75 peptide in particularly a HER2/neu E75 peptide and/or a modified which a part of amino acids thereofare substituted or modi HER2/neu E75 peptide, and a cellular immunity induction fied are useful as cancer vaccines. promoter. 0004. It is also known that an adjuvant is utilized in order to enhance the action as cancer vaccine of the HER2/neu E75 BACKGROUND ART peptide. The HER2/neu E75 peptide has been investigated 0002 There are a cancer vaccine that prevents viral infec and reported to involve immunization by injection, and GM tion to prevent a cancer caused by the virus, and a cancer CSF is known as an adjuvant to be used on that occasion. vaccine which provides the result that cancer cells are spe 0005. In general, vaccines are administered by subcutane cifically attacked by the immune system via the recognition of ous or intradermal injection. In addition to those routes, a cancer-specific antigen by the immune mechanism, particu immunity induction by a various of administration route, for larly the cellular immune mechanism in which cytotoxic T example, transdermal administration (Patent Document 1 and cells (CTLs) play an important role. The former is not effec Non-Patent Document 1); and mucosal administration Such tive at all for a cancer in which the virus does not participate. as buccal administration, nasal administration, and Sublin The latter is a cancer therapeutic strategy of targeting an gual administration (Non-Patent Document 2, Patent Docu antigen possessed by a cancer cell itself. It is considered that ment 2, and Patent Document 3) have been tried. the latter is widely effective for cancers having antigen by specifying the antigen. Interalia, a cancer Vaccine based on LIST OF DOCUMENTS the viewpoint of the latter can treat tumors that are difficult to 0006 Patent Document 1 US Patent Application Publi remove by Surgical operation because of their size, and causes cation No. US 2008/O1934.87 less side effects as compared with the conventional therapies 0007 Patent Document 2.JP 2002-53.1415A Such as chemotherapy and radiation therapy. 0008 Patent Document 3 US Patent Application Publi 0003) A HER2/neugene is amplified and overexpressed in cation No. US 2008/O112974 various adenocarcinomas including breast cancer. Those can 0009 Patent Document 4.JP 7-505883 A cers overproduce the HER2/neu protein. The HER2/neu pro O010 Patent Document 5 JP 2007-529531 A tein is fragmented in the cancer cell to produce partial pep 0011 Non-Patent Document 1 Hosoi Akihiro et al., Can tides containing 8 to 12 amino acids. A HER2/neu peptide is cer Research, 68,3941-3949 (2008) one of the peptide fragment which has been bound with the 0012 Non-Patent Document 2 Zhengrong Cui et al., MHC class I molecule in a cancer cell, moved to the surface Pharmaceutical Research, Vol. 19, No. 7, 947-953 (2002) of the cancer cell, and presented as an antigen bound to the 0013 Non-Patent Document 3 Mittendorf E A et al., MHC class I molecule on the cancer cell surface. The peptide Cancer Immunol Immunother, 57(10), 1511-1521 (2008) becomes a mark of the cancer cell. The HER2/neu E75 pep tide, which is a HLA-A2 or A3 haplotype MHC restricted 0014 Non-Patent Document 4 George EP et al., Journal peptide, is considered as a particularly promising HER2/neu of Clinical Oncology, 23(30), 7536-7545 (2005) peptide because it is reported to be effective in clinical tests. SUMMARY OF THE INVENTION The amino acid sequence of the HER2/neu E75 peptide is Lys-Ile-Phe-Gly-Ser-Leu-Ala-Phe-Leu (SEQ ID NO: 1). 0015. It is well known that an adjuvant is used to enhance When HER2/neu E75 peptide, or a modified HER2/neu E75 efficacy of a vaccine. Suitable adjuvant generally vary peptide in which a part of amino acids of the HER2/neu E75 depending on, for example, the kind of the antigen, the peptide is substituted or modified is administered to a living administration route, and the immune response which is body as an antigen (herein, the HER2/neu E75 peptide or desired to be induced (that is, cellular immunity or humoral modified HER2/neu E75 peptide which has been adminis immunity). Further, in addition to the adjuvant, there are a tered as an antigen is referred to as “E75 antigen peptide'), the variety of substances which promote the induction of the E75 antigen peptide is bound to the MHC class I molecule on immunity. Thus, an object of the present invention is to pro the Surface of a dendritic cell which is an antigen presenting vide a composition for use as a cancer vaccine, which has cell, or the E75 antigen peptide is once taken into a dendritic higher efficacy and is convenient for use. cell, bound to the MHC class I molecule of the dendritic cell, 0016. A microorganism or a virus itself, or a part of them and then, is moved to the surface of the dendritic cell, thereby, is contained in a widely used vaccine and the vaccine is is presented as an antigenbound to the MHC class I molecule administered to induce immune response. Usually, since on the surface of the dendritic cell. An activated dendritic cell invasion of the microorganism or virus is inhibited by the skin having the E75 antigen peptide/MHC class I molecule com due to the size thereof, it is difficult that the vaccine is admin plex is moved to the regional lymph node, and activates a istered on the skin. Furthermore, it is also difficult to admin CD8-positive T lymphocyte which recognizes the E75 anti ister the vaccine orally because the microorganism or virus is gen peptide/MHC class I molecule complex to differentiate decomposed by gastric acid and digestive . There and proliferate the CD8-positive T lymphocyte into a cyto fore, injectable formulations which are invasively adminis toxic T-cell (CTL). The CTL recognizes tumor cells having tered into the body have been generally utilized. However, the the complex of HER2/neu E75 peptide (derived from the injection has some problems including pain, fear, injection endogenous HER2/neu protein) of the same amino acid scar, and Subsequent Scarring cicatrization. People other than US 2014/0220079 A1 Aug. 7, 2014 healthcare workers are not permitted to perform the injection. agonists; adrenaline receptor antagonists such as C.1 receptor Intradermal injection which can introduce higher immune antagonists, B1 receptor antagonists, B2 receptor antagonists, response is a difficult administration technique. There is a risk and B3 receptor antagonists; adrenaline receptor agonists of accidental infection of the health care workers due to Such as C.1 receptoragonists and C2 receptoragonists; angio needlestick injury. Patients are needed to visit the hospital tensin receptor agonists such as AT2 receptor agonists; repeatedly when administration is performed repetitively. GABA receptor agonists such as GABA receptor agonists; Medical wastes which necessitate special disposition Such as thrombin receptor antagonists such as PAR-1 receptor injection needles are generated. In view of the above issues, antagonists; thrombin receptoragonists Such as PAR-1 recep injection is not necessarily the optimal administration route. toragonists; opioid receptoragonists Such as buprenorphine; 0017. A HER2/neu E75 peptide and/or a modified HER2/ leukotriene receptor antagonists such as CySLT1 receptor neu E75 peptide can activate CTLs (cytotoxic T-cells) via antagonists and CysLT2 receptor antagonists; leukotriene MHC class I molecules. Furthermore, since HER2/neu E75 receptor agonists such as BLT receptor agonists; ADP recep peptide is a molecule consisting of 9 amino acids and having toragonists Such as adenosine diphosphate; melatonin recep a molecular weight of about 1000, and is significantly smaller toragonists Such as melatonin; receptoragonists than microorganisms or virus itself although they are not Such as octreotide; cannabinoid receptor agonists such as considered as a small molecular Substance. It may be possible dronabinol; Sphingosine-1 phosphate receptor agonists Such that they are administered by a route other than injection. as fingolimod; metabotropic glutamate receptor agonists However, a preparation for the administration of the peptide Such as mGluR2 receptor agonists, mGluR3 receptor ago vaccine in a rout other than injection has not been developed nists, mGluR4 receptor agonists, mGluR6 receptor agonists, yet. The reason includes manythings, for example: a Suitable mGluR7 receptor agonists, and mGluR8 receptor agonists; Substance that can promote to induce the cellular immunity phospholipase A2 inhibitors such as glycyrrhizic acid; has been unknown; it has also been unknown whether or not TGF-(3 production inhibitors such as pirfenidone; Th2 cytok an antigen can be delivered to a tissue Suitable for the induc ine inhibitors such as Suplatast tosylate; pharmacologically tion of the cellular immunity. Interalia, a Substance that can acceptable acids such as decanoic acid, lauric acid, myristic promote to induce the cellular immunity when it is used with acid, isostearic acid and oleic acid, or pharmacologically the antigen when administered in a route other than injection acceptable salts thereof; and helper such as Peptide has been unknown. 25. 0018. The inventors have found that the immunity can 0019. In regard to oral mucosal administration, it was also effectively be induced by mucosal administration of the pep found that it is particularly suitable to use TLR1/2 ligands tide vaccine. The inventors also found some Substances Suit such as Pam CSK, TLR7 and/or TLR8 ligands such as imi able for enhancing immunity induced by the mucosal admin quimod and residuimod; cyclic dinucleotides such as cyclic istration of a HER2/neu E75 peptide and/or a modified di-GMP and cyclic di-AMP; immunomodulatory small mol HER2/neu E75 peptide. The substances may include TLR ecule drugs such as levamisole hydrochloride; cyclooxyge ligands such as Pam CSK, poly(I:C), lipopolysaccharides, nase inhibitors such as etodolac and loxoprofen; prostaglan imiquimod and residuimod; cyclic dinucleotides such as din receptor antagonists such as EP2 receptor antagonists, cyclic di-GMP and cyclic di-AMP; immunomodulatory EP4 receptor antagonists, DP receptor antagonists, and IP Small molecule drugs such as levamisole hydrochloride; receptor antagonists; prostaglandin receptor agonists such as cyclooxygenase inhibitors such as etodolac and loxoprofen; EP3 receptor agonists; TSLP production inhibitors such as prostaglandin receptor antagonists such as EP2 receptor berberine chloride and maringenin; adenylate cyclase inhibi antagonists, EP4 receptor antagonists, DP receptor antago tors such as 2.5'-dideoxyadenosine and niacin: omega-3 fatty nists, and IP receptor antagonists; prostaglandin receptor acids such as eicosapentaenoic acid and docosahexaenoic agonists such as EP3 receptor agonists; TSLP production acid; PPAR agonists such as PPAR-a agonists, PPAR-6 ago inhibitors such as berberine chloride and maringenin; adeny nists and PPAR-Y agonists; dopamine receptor antagonists late cyclase inhibitors such as 2',5'-dideoxyadenosine and Such as D1 receptor antagonists and D5 receptor antagonists; niacin: omega-3 fatty acids such as eicosapentaenoic acid and dopamine receptoragonists such as D2 receptoragonists, D3 docosahexaenoic acid; PPAR agonists such as PPAR-a ago receptoragonists, and D4 receptoragonists; histamine recep nists, PPAR-8 agonists, and PPAR-Y agonists; dopamine torantagonists such as H1 receptor antagonists and H2 recep receptor antagonists such as D1 receptor antagonists and D5 torantagonists; histamine receptoragonists such as H1 recep receptor antagonists; dopamine receptor agonists such as D2 toragonists, H3 receptor agonists, and H4 receptor agonists; receptoragonists, D3 receptoragonists, and D4 receptorago serotonin receptor antagonists such as 5-HT2 receptor nists; histamine receptor antagonists such as H1 receptor antagonists, 5-HT4 receptor antagonists, 5-HT6 receptor antagonists and H2 receptor antagonists; histamine receptor antagonists and 5-HT7 receptor antagonists; serotonin recep agonists such as H1 receptor agonists, H3 receptor agonists, tor agonists such as 5-HT1 receptor agonists and 5-HT2 and H4 receptoragonists; serotonin receptor antagonists Such receptor agonists; receptor antagonists such as as 5-HT2 receptor antagonists, 5-HT4 receptor antagonists, V2 receptor antagonists; vasopressin receptor agonists Such 5-HT6 receptor antagonists, and 5-HT7 receptor antagonists; as V1 receptoragonists; muscarine receptor antagonists Such serotonin receptor agonists such as 5-HT1 receptor agonists as M1 receptor antagonists, M3 receptor antagonists, and M5 and 5-HT2 receptor agonists; vasopressin receptor antago receptor antagonists; muscarine receptoragonists such as M1 nists such as V2 receptor antagonists; vasopressin receptor receptor agonists, M2 receptor agonists, M3 receptor ago agonists such as V1 receptor agonists; muscarine receptor nists, M4 receptor agonists, and M5 receptor agonists; antagonists such as M1 receptor antagonists, M3 receptor adrenaline receptor antagonists Such as C.1 receptor antago antagonists, and M5 receptor antagonists; muscarine receptor nists, B1 receptor antagonists, B2 receptorantagonists, and B3 agonists such as M1 receptoragonists, M2 receptoragonists, receptor antagonists; adrenaline receptoragonists such as C.1 M3 receptoragonists, M4 receptoragonists, and M5 receptor receptor agonists and C2 receptor agonists; angiotensin US 2014/0220079 A1 Aug. 7, 2014

receptor agonists such as AT2 receptor agonists; GABA inhibitor and a helper peptide, and a combination of a phar receptoragonists such as GABA receptoragonists; thrombin macologically acceptable acid or a pharmacologically receptor antagonists such as PAR-1 receptor antagonists; acceptable salt thereof and a helper peptide. thrombin receptoragonists such as PAR-1 receptor agonists; 0020. In regard to nasal mucosal administration, it was opioid receptor agonists Such as buprenorphine; leukotriene found that it is particularly suitable to use TLR1/2 ligands receptor antagonists such as CySLT1 receptor antagonists and such as Pam CSK; TLR3 ligands such as poly(I:C); TLR4 CysLT2 receptor antagonists; leukotriene receptor agonists ligands Such as lipopolysaccharides; cyclic dinucleotides Such as BLT receptoragonists; ADP receptoragonists such as such as cyclic di-GMP and cyclic di-AMP; cyclooxygenase adenosine diphosphate; melatonin receptor agonists such as inhibitors such as etodolac and loxoprofen; prostaglandin melatonin; Somatostatin receptoragonists such as octreotide; receptor antagonists such as EP2 receptor antagonists, EP4 cannabinoid receptor agonists such as dronabinol; Sphin receptorantagonists, DP receptorantagonists, and IP receptor gosine-1 phosphate receptor agonists such as fingolimod: antagonists; prostaglandin receptor agonists such as EP3 metabotropic glutamate receptor agonists such as mGluR2 receptor agonists; TSLP production inhibitors such as ber receptoragonists, mGluR3 receptoragonists, mGluR4 recep berine chloride and naringenin; adenylate cyclase inhibitors tor agonists, mGluR6 receptor agonists, mGluR7 receptor Such as 2.5'-dideoxyadenosine and niacin; omega-3 fatty agonists, and mGluR8 receptor agonists; phospholipase A2 acids such as eicosapentaenoic acid and docosahexaenoic inhibitors such as glycyrrhizic acid; TGF-B production acid; PPAR agonists such as PPAR-O. agonists, PPAR-8 ago inhibitors such as pirfenidone: Th2 cytokine inhibitors such nists and PPAR-Y agonists; dopamine receptor antagonists as Suplatast tosylate; helper peptides; or combinations of two Such as D1 receptor antagonists and D5 receptor antagonists; or more of them. Furthermore, it was also found that cellular dopamine receptoragonists such as D2 receptoragonists, D3 immunity is markedly enhanced by a combination of a TLR receptoragonists, and D4 receptoragonists; histamine recep ligandanda helperpeptide, a combination of a cyclic dinucle torantagonists such as H1 receptor antagonists and H2 recep otide and a helper peptide, a combination of an immuno torantagonists; histamine receptoragonists such as H1 recep modulatory Small molecule drug and a helper peptide, a com toragonists, H3 receptor agonists, and H4 receptor agonists; bination of a cyclooxygenase inhibitor and a helperpeptide, a serotonin receptor antagonists such as 5-HT2 receptor combination of a prostaglandin receptor antagonist and a antagonists, 5-HT4 receptor antagonists, 5-HT6 receptor helper peptide, a combination of a prostaglandin receptor antagonists and 5-HT7 receptor antagonists; serotonin recep agonist and a helper peptide, a combination of a TSLP pro tor agonists such as 5-HT1 receptor agonists and 5-HT2 duction inhibitor and a helper peptide, a combination of an receptor agonists; Vasopressin receptor antagonists such as adenylate cyclase inhibitor and a helper peptide, a combina V2 receptor antagonists; vasopressin receptor agonists Such tion of an omega-3 fatty acid and a helper peptide, a combi as V1 receptoragonists; muscarine receptor antagonists Such nation of a PPAR agonistanda helper peptide, a combination as M1 receptor antagonists, M3 receptor antagonists, and M5 of a dopamine receptor antagonist and a helper peptide, a receptor antagonists; muscarine receptoragonists such as M1 combination of a dopamine receptor agonist and a helper receptor agonists, M2 receptor agonists, M3 receptor ago peptide, a combination of a histamine receptor agonist and a nists, M4 receptor agonists, and M5 receptor agonists; helperpeptide, a combination of a histamine receptor antago adrenaline receptor antagonists Such as C.1 receptor antago nist and a helper peptide, a combination of a serotonin recep nists, B1 receptor antagonists, B2 receptorantagonists, and B3 toragonist and a helper peptide, a combination of a serotonin receptor antagonists; adrenaline receptoragonists such as C.1 receptor antagonist and a helper peptide, a combination of a receptor agonists and C2 receptor agonists; angiotensin vasopressin receptor antagonist and a helper peptide, a com receptor agonists such as AT2 receptor agonists; GABA bination of a vasopressin receptor agonist and a helper pep receptoragonists such as GABA receptoragonists; thrombin tide, a combination of a muscarine receptor antagonist and a receptor antagonists such as PAR-1 receptor antagonists; helperpeptide, a combination of a muscarine receptoragonist thrombin receptoragonists such as RAR-1 receptoragonists; and a helper peptide, a combination of an adrenaline receptor opioid receptor agonists Such as buprenorphine; leukotriene antagonist and a helper peptide, a combination of an adrena receptor antagonists such as CysLT1 receptor antagonists and line receptoragonistandahelperpeptide, a combination of an CysLT2 receptor antagonists; leukotriene receptor agonists angiotensin receptor agonist and a helper peptide, a combi Such as BLT receptoragonists; ADP receptoragonists such as nation of a GABA receptor agonist and a helper peptide, a adenosine diphosphate; melatonin receptor agonists such as combination of a thrombin receptor antagonist and a helper melatonin; somatostatin receptoragonists such as octreotide; peptide, a combination of a thrombin receptor agonist and a cannabinoid receptor agonists such as dronabinol; Sphin helper peptide, a combination of an opioid receptor agonist gosine-1 phosphate receptor agonists such as fingolimod: and a helper peptide, a combination of an ADP receptor metabotropic glutamate receptor agonists such as mGluR2 agonist and a helper peptide, a combination of a leukotriene receptoragonists, mGluR3 receptoragonists, mGluR4 recep receptor antagonist and a helper peptide, a combination of a tor agonists, mGluR6 receptor agonists, mGluR7 receptor leukotriene receptoragonist and a helperpeptide, a combina agonists, and mGluR8 receptor agonists; phospholipase A2 tion of a melatonin receptor agonist and a helper peptide, a inhibitors such as glycyrrhizic acid; TGF-B production combination of a Somatostatin receptor agonist and a helper inhibitors such as pirfenidone: Th2 cytokine inhibitors such peptide, a combination of a cannabinoid receptoragonist and as Suplatast tosylate; helper peptides; or combinations of two a helperpeptide, a combination of a sphingosine-1 phosphate or more of them. receptor agonist and a helper peptide, a combination of a 0021. Furthermore, it was also found that cellular immu metabotropic glutamate receptor agonist and a helper pep nity is markedly enhanced by a combination of a TLR ligand tide, a combination of a phospholipase A2 inhibitor and a and a helper peptide, a combination of a cyclic dinucleotide helper peptide, a combination of a TGF-3 production inhibi and a helperpeptide, a combination of an immunomodulatory tor and a helper peptide, a combination of a Th2 cytokine Small molecule drug and a helper peptide, a combination of a US 2014/0220079 A1 Aug. 7, 2014 cyclooxygenase inhibitor and a helper peptide, a combination agonist, a leukotriene receptor antagonist, a leukotriene of a prostaglandin receptor antagonistanda helper peptide, a receptoragonist, a melatonin receptoragonist, a Somatostatin combination of a prostaglandin receptoragonist and a helper receptor agonist, a cannabinoid receptor agonist, a sphin peptide, a combination of a TSLP production inhibitor and a gosine-1 phosphate receptor agonist, a metabotropic helper peptide, a combination of an adenylate cyclase inhibi glutamate receptor agonist, a phospholipase A2 inhibitor, a tor and a helper peptide, a combination of an omega-3 fatty TGF-B production inhibitor, a Th2 cytokine inhibitor, and acid and a helper peptide, a combination of a PPAR agonist combinations of two or more of them; and a helper peptide, a combination of a dopamine receptor (2) the cancer vaccine composition for mucosal administra antagonistanda helperpeptide, a combination of a dopamine tion according to (1), further comprising a pharmacologically receptor agonist and a helper peptide, a combination of a acceptable acid or a pharmacologically acceptable salt histamine receptor agonist and a helper peptide, a combina thereofas a second cellular immunity induction promoter, tion of a histamine receptor antagonistanda helperpeptide, a (3) the cancer vaccine composition for mucosal administra combination of a serotonin receptor agonist and a helper tion according to (1) or (2), wherein the first cellular immu peptide, a combination of a serotonin receptor antagonistand nity induction promoter is a TLR ligand; a helper peptide, a combination of a vasopressin receptor (4) the cancer vaccine composition for mucosal administra antagonist and a helper peptide, a combination of a vaso tion according to (1) or (2), wherein the first cellular immu pressin receptor agonist and a helper peptide, a combination nity induction promoter is a cyclic dinucleotide; of a muscarine receptor antagonist and a helper peptide, a 0023 (5) the cancer vaccine composition for mucosal combination of a muscarine receptor agonist and a helper administration according to (1) or (2), wherein the first peptide, a combination of an adrenaline receptor antagonist cellular immunity induction promoter is an immunomodu and a helper peptide, a combination of an adrenaline receptor latory Small molecule drug; agonistanda helper peptide, a combination of an angiotensin (6) the cancer vaccine composition for mucosal administra receptor agonist and a helper peptide, a combination of a tion according to (1) or (2), wherein the first cellular immu GABA receptor agonist and a helper peptide, a combination nity induction promoter is a cyclooxygenase inhibitor; of a thrombin receptor antagonist and a helper peptide, a (7) the cancer vaccine composition for mucosal administra combination of a thrombin receptor agonist and a helper tion according to (1) or (2), wherein the first cellular immu peptide, a combination of an opioid receptor agonist and a nity induction promoter is a prostaglandin receptor antago helperpeptide, a combination of an ADP receptoragonistand nist, and the prostaglandin receptor antagonist is an EP2 a helper peptide, a combination of a leukotriene receptor receptor antagonist, an EP4 receptor antagonist, a DP recep antagonist and a helper peptide, a combination of a leukot tor antagonist or an IP receptor antagonist; riene receptor agonist and a helper peptide, a combination of (8) the cancer vaccine composition for mucosal administra a melatonin receptor agonist and a helper peptide, a combi tion according to (1) or (2), wherein the first cellular immu nation of a Somatostatin receptoragonistandahelper peptide, nity induction promoter is a prostaglandin receptor agonist, a combination of a cannabinoid receptoragonist and a helper and the prostaglandin receptor agonist is an EP3 receptor peptide, a combination of a sphingosine-1 phosphate receptor agonist, agonistanda helperpeptide, a combination of a metabotropic (9) the cancer vaccine composition for mucosal administra glutamate receptor agonist and a helper peptide, a combina tion according to (1) or (2), wherein the first cellular immu tion of a phospholipase A2 inhibitor and a helper peptide, a nity induction promoter is a TSLP production inhibitor; combination of a TGF-B production inhibitor and a helper (10) the cancer vaccine composition for mucosal administra peptide, a combination of Th2 cytokine inhibitor and a helper tion according to (1) or (2), wherein the first cellular immu peptide, and a combination of a pharmacologically accept nity induction promoter is an adenylate cyclase inhibitor; able acid or a pharmacologically acceptable salt thereofanda (11) the cancer vaccine composition for mucosal administra helper peptide. tion according to (1) or (2), wherein the first cellular immu 0022. Therefore, the present invention, in a first aspect, nity induction promoter is an omega-3 fatty acid; provides the aspects listed below: (12) the cancer vaccine composition for mucosal administra (1) a cancer vaccine composition for mucosal administration, tion according to (1) or (2), wherein the first cellular immu comprising: nity induction promoter is a PPAR agonist, and the PPAR (i) a HER2/neu E75 peptide and/or a modified HER2/neu E75 agonist is a PPAR-O. agonist, a PPAR-8 agonist, or a PPAR-y peptide; and agonist, (ii) a first cellular immunity induction promoter selected from (13) the cancer vaccine composition for mucosal administra a TLR ligand, a cyclic dinucleotide, a helper peptide, an tion according to (1) or (2), wherein the first cellular immu immunomodulatory Small molecule drug, a cyclooxygenase nity induction promoter is a dopamine receptor antagonist, inhibitor, a prostaglandin receptorantagonist, a prostaglandin and the dopamine receptorantagonist is a D1 receptorantago receptor agonist, a TSLP production inhibitor, an adenylate nist or a D5 receptor antagonist; cyclase inhibitor, an omega-3 fatty acid, a PPAR agonist, a (14) the cancer vaccine composition for mucosal administra dopamine receptor antagonist, a dopamine receptoragonist, a tion according to (1) or (2), wherein the first cellular immu histamine receptoragonist, a histamine receptor antagonist, a nity induction promoter is a dopamine receptor agonist, and serotonin receptoragonist, a serotonin receptor antagonist, a the dopamine receptor agonist is a D2 receptoragonist, a D3 vasopressin receptor antagonist, a vasopressin receptor ago receptor agonist, or a D4 receptor agonist; nist, a muscarine receptor antagonist, a muscarine receptor (15) the cancer vaccine composition for mucosal administra agonist, an adrenaline receptor antagonist, an adrenaline tion according to (1) or (2), wherein the first cellular immu receptor agonist, an angiotensin receptor agonist, a GABA nity induction promoter is a histamine receptor antagonist, receptor agonist, a thrombin receptor antagonist, a thrombin and the histamine receptorantagonist is a H1 receptorantago receptoragonist, an opioid receptoragonist, an ADP receptor nist or a H2 receptor antagonist; US 2014/0220079 A1 Aug. 7, 2014

(16) the cancer vaccine composition for mucosal administra nity induction promoter is a thrombin receptor agonist, and tion according to (1) or (2), wherein the first cellular immu the thrombin receptor agonist is a PAR-1 receptor agonist; nity induction promoter is a histamine receptor agonist, and (29) the cancer vaccine composition for mucosal administra the histamine receptor agonist is a H1 receptoragonist, a H3 tion according to (1) or (2), wherein the first cellular immu receptor agonist or a H4 receptor agonist; nity induction promoter is an opioid receptor agonist; (17) the cancer vaccine composition for mucosal administra (30) the cancer vaccine composition for mucosal administra tion according to (1) or (2), wherein the first cellular immu tion according to (1) or (2), wherein the first cellular immu nity induction promoter is a serotonin receptor antagonist, nity induction promoter is a leukotriene receptor antagonist, and the serotonin receptor antagonist is a 5-HT2 receptor and the leukotriene receptor antagonist is a CySLT1 receptor antagonist, a 5-HT4 receptor antagonist, a 5-HT6 receptor antagonist or a CySLT2 receptor antagonist; antagonist, or a 5-HT7 receptor antagonist; (31) the cancer vaccine composition for mucosal administra (18) the cancer vaccine composition for mucosal administra tion according to (1) or (2), wherein the first cellular immu tion according to (1) or (2), wherein the first cellular immu nity induction promoter is a leukotriene receptoragonist, and nity induction promoter is a serotonin receptor agonist, and the leukotriene receptor agonist is a BLT receptor agonist; the serotonin receptor agonist is a 5-HT1 receptor agonist or (32) the cancer vaccine composition for mucosal administra a 5-HT2 receptor agonist; tion according to (1) or (2), wherein the first cellular immu (19) the cancer vaccine composition for mucosal administra nity induction promoter is a melatonin receptor agonist; tion according to (1) or (2), wherein the first cellular immu (33) the cancer vaccine composition for mucosal administra nity induction promoter is a vasopressin receptor antagonist, tion according to (1) or (2), wherein the first cellular immu and the vasopressin receptor antagonist is a V2 receptor nity induction promoter is a Somatostatin receptor agonist; antagonist; (34) the cancer vaccine composition for mucosal administra (20) the cancer vaccine composition for mucosal administra tion according to (1) or (2), wherein the first cellular immu tion according to (1) or (2), wherein the first cellular immu nity induction promoter is a cannabinoid receptor agonist; nity induction promoter is a vasopressin receptoragonist, and (35) the cancer vaccine composition for mucosal administra the vasopressin receptor agonist is a V1 receptor agonist; tion according to (1) or (2), wherein the first cellular immu (21) the cancer vaccine composition for mucosal administra nity induction promoter is a sphingosine-1 phosphate recep tion according to (1) or (2), wherein the first cellular immu toragonist; nity induction promoter is a muscarine receptor antagonist, (36) the cancer vaccine composition for mucosal administra and the muscarine receptor antagonist is a M1 receptor tion according to (1) or (2), wherein the first cellular immu antagonist, a M3 receptor antagonist, or a M5 receptor nity induction promoter is a metabotropic glutamate receptor antagonist; agonist, and the metabotropic glutamate receptor agonist is a (22) the cancer vaccine composition for mucosal administra mGluR2 receptor agonist, a mGluR3 receptor agonist, a tion according to (1) or (2), wherein the first cellular immu mGluR4 receptor agonist, a mGluR6 receptor agonist, a nity induction promoter is a muscarine receptor agonist, and mGluR7 receptor agonist, or a mGluR8 receptor agonist; the muscarine receptoragonist is a M1 receptoragonist, a M2 (37) the cancer vaccine composition for mucosal administra receptor agonist, a M3 receptor agonist, a M4 receptor ago tion according to (1) or (2), wherein the first cellular immu nist, or a M5 receptor agonist; nity induction promoter is an ADP receptor agonist; (23) the cancer vaccine composition for mucosal administra (38) the cancer vaccine composition for mucosal administra tion according to (1) or (2), wherein the first cellular immu tion according to (1) or (2), wherein the first cellular immu nity induction promoter is an adrenaline receptor antagonist, nity induction promoter is a phospholipase A2 inhibitor, and the adrenaline receptor antagonist is an C.1 receptor (39) the cancer vaccine composition for mucosal administra antagonist, a B1 receptor antagonist, a B2 receptor antagonist, tion according to (1) or (2), wherein the first cellular immu or a 33 receptor antagonist; nity induction promoter is a TGF-3 production inhibitor; (24) the cancer vaccine composition for mucosal administra (40) the cancer vaccine composition for mucosal administra tion according to (1) or (2), wherein the first cellular immu tion according to (1) or (2), wherein the first cellular immu nity induction promoter is an adrenaline receptoragonist, and nity induction promoter is a Th2 cytokine inhibitor; the adrenaline receptoragonist is an O.1 receptoragonist oran (41) the cancer vaccine composition for mucosal administra C2 receptor agonist; tion according to (1) or (2), wherein the first cellular immu (25) the cancer vaccine composition for mucosal administra nity induction promoter is a helper peptide; tion according to (1) or (2), wherein the first cellular immu (42) the cancer vaccine composition for mucosal administra nity induction promoter is an angiotensin receptor agonist, tion according to (1) or (2), wherein the first cellular immu and the angiotensin receptor agonist is an AT2 receptor ago nity induction promoter is a combination of a helper peptide nist; and one or more substances selected from the group consist (26) the vaccine composition for mucosal administration ing of a TLR ligand, a cyclic dinucleotide, an immunomodu according to (1) or (2), wherein the first cellular immunity latory Small molecule drug, a cyclooxygenase inhibitor, a induction promoter is a GABA receptor agonist, and the prostaglandin receptor antagonist, a prostaglandin receptor GABA receptor agonist is a GABA receptor agonist; agonist, a TSLP production inhibitor, an adenylate cyclase (27) the cancer vaccine composition for mucosal administra inhibitor, an omega-3 fatty acid, a PPAR agonist, a dopamine tion according to (1) or (2), wherein the first cellular immu receptor antagonist, a dopamine receptoragonist, a histamine nity induction promoter is a thrombin receptor antagonist, receptoragonist, a histamine receptor antagonist, a serotonin and the thrombin receptor antagonist is a PAR-1 receptor receptor agonist, a serotonin receptor antagonist, a vaso antagonist; pressin receptor antagonist, a vasopressin receptor agonist, a (28) the cancer vaccine composition for mucosal administra muscarine receptor antagonist, a muscarine receptor agonist, tion according to (1) or (2), wherein the first cellular immu an adrenaline receptorantagonist, an adrenaline receptorago US 2014/0220079 A1 Aug. 7, 2014 nist, an angiotensin receptor agonist, a GABA receptor ago nist, a prostaglandin receptor agonist, a TSLP production nist, a thrombin receptor antagonist, a thrombin receptorago inhibitor, an adenylate cyclase inhibitor, an omega-3 fatty nist, an opioid receptor agonist, an ADP receptor agonist, a acid, a PPAR agonist, a dopamine receptor antagonist, a leukotriene receptor antagonist, a leukotriene receptor ago dopamine receptor agonist, a histamine receptor agonist, a nist, a melatonin receptor agonist, a Somatostatin receptor histamine receptor antagonist, a serotonin receptoragonist, a agonist, a cannabinoid receptor agonist, a sphingosine-1 serotonin receptor antagonist, a vasopressin receptor antago phosphate receptor agonist, a metabotropic glutamate recep nist, a vasopressin receptor agonist, a muscarine receptor toragonist, a phospholipase A2 inhibitor, a TGF-B production antagonist, a muscarine receptoragonist, an adrenaline recep inhibitor and a Th2 cytokine inhibitor; tor antagonist, an adrenaline receptoragonist, an angiotensin (43) a cancer vaccine film formulation for mucosal adminis receptoragonist, a GABA receptoragonist, a thrombin recep tration, comprising the pharmaceutical composition accord torantagonist, a thrombin receptoragonist, an opioid receptor ing to any one of (1) to (42) and being in the form of a film agonist, an ADP receptor agonist, a leukotriene receptor formulation; antagonist, a leukotriene receptoragonist, a melatonin recep (44) a cancer vaccine liquid formulation for mucosal admin tor agonist, a Somatostatin receptor agonist, a cannabinoid istration, comprising the pharmaceutical composition receptoragonist, a sphingosine-1 phosphate receptoragonist, according to any one of (1) to (42) and being in the form of a a metabotropic glutamate receptor agonist, a phospholipase liquid formulation; and A2 inhibitor, a TGF-(3 production inhibitor, a Th2 cytokine (45) a cancer vaccine orally-disintegrating tablet for mucosal inhibitor, and a combination of two or more of them, as administration, comprising the pharmaceutical composition cellular immunity induction promoters for a HER2/neu E75 according to any one of (1) to (42) and being in the form of an peptide and/or a modified HER2/neu E75 peptide. Therefore, orally-disintegrating tablet. the present invention also provides the following embodi 0024. According to another aspect, the cancer vaccine ment: composition of the present invention can be used for the (48) ATLR ligand, a cyclic dinucleotide, a helper peptide, an treatment or prevention of cancer. Therefore, the present immunomodulatory Small molecule drug, a cyclooxygenase invention also provides the following embodiments: inhibitor, a prostaglandin receptorantagonist, a prostaglandin (46) a method for treating or preventing cancer in a Subject, receptor agonist, a TSLP production inhibitor, an adenylate comprising mucosally administering to the Subject a thera cyclase inhibitor, an omega-3 fatty acid, a PPAR agonist, a peutically effective amounts of (i) a HER2/neu E75 peptide dopamine receptor antagonist, a dopamine receptoragonist, a and/or a modified HER2/neu E75 peptide, and (ii) a cellular histamine receptoragonist, a histamine receptor antagonist, a immunity induction promoter selected from a TLR ligand, serotonin receptoragonist, a serotonin receptor antagonist, a acyclic dinucleotide, a helperpeptide, an immunomodulatory vasopressin receptor antagonist, a vasopressin receptor ago Small molecule drug, a cyclooxygenase inhibitor, a prostag nist, a muscarine receptor antagonist, a muscarine receptor landin receptorantagonist, a prostaglandin receptoragonist, a agonist, an adrenaline receptor antagonist, an adrenaline TSLP production inhibitor, an adenylate cyclase inhibitor, an receptor agonist, an angiotensin receptor agonist, a GABA omega-3 fatty acid, a PPAR agonist, a dopamine receptor receptor agonist, a thrombin receptor antagonist, a thrombin antagonist, a dopamine receptoragonist, a histamine receptor receptoragonist, an opioid receptoragonist, an ADP receptor agonist, a histamine receptor antagonist, a serotonin receptor agonist, a leukotriene receptor antagonist, a leukotriene agonist, a serotonin receptor antagonist, a vasopressin recep receptoragonist, a melatonin receptoragonist, a Somatostatin tor antagonist, a vasopressin receptor agonist, a muscarine receptor agonist, a cannabinoid receptor agonist, a sphin receptor antagonist, a muscarine receptoragonist, an adrena gosine-1 phosphate receptor agonist, a metabotropic line receptor antagonist, an adrenaline receptor agonist, an glutamate receptor agonist, a phospholipase A2 inhibitor, a angiotensin receptor agonist, a GABA receptor agonist, a TGF-B production inhibitor, a Th2 cytokine inhibitor, or a thrombin receptor antagonist, a thrombin receptoragonist, an combination of two or more of them, for the use as a cellular opioid receptor agonist, an ADP receptor agonist, a leukot immunity induction promoter for mucosal administration of a riene receptor antagonist, a leukotriene receptor agonist, a HER2/neu E75 peptide and/or a modified HER2/neu E75 melatonin receptoragonist, a Somatostatin receptoragonist, a peptide. cannabinoid receptor agonist, a sphingosine-1 phosphate 0026. The present invention also provides the following receptoragonist, a metabotropic glutamate receptoragonist, a embodiments: phospholipase A2 inhibitor, a TGF-3 production inhibitor, a (49) A method of inducing cellular immunity, comprising Th2 cytokine inhibitor, and a combination of two or more of mucosally administering to a subject (i) HER2/neu E75 pep them; and tide and/or a modified HER2/neu E75 peptide and (ii) a first (47) a method for treating or preventing cancer in a Subject, cellular immunity induction promoter selected from TLR comprising administering to the Subject a therapeutically ligand, cyclic dinucleotide, helper peptide, immunomodula effective amount of the cancer vaccine composition for tory Small molecule drug, cyclooxygenase inhibitor, prostag mucosal administration according to any one of (1) to (42), landin receptor antagonist, prostaglandin receptor agonist, the cancer vaccine film formulation for mucosal administra TSLP production inhibitor, adenylate cyclase inhibitor, tion according to (43), the cancer vaccine liquid formulation omega-3 fatty acid, PPAR agonist, dopamine receptor for mucosal administration according to (44), or the cancer antagonist, dopamine receptor agonist, histamine receptor vaccine orally-disintegrating tablet for mucosal administra agonist, histamine receptor antagonist, serotonin receptor tion according to (45). agonist, serotonin receptor antagonist, vasopressin receptor 0025. According to another aspect, the present invention antagonist, vasopressin receptoragonist, muscarine receptor also provides a TLR ligand, a cyclic dinucleotide, a helper antagonist, muscarine receptor agonist, adrenalin receptor peptide, an immunomodulatory Small molecule drug, a antagonist, adrenalin receptor agonist, angiotensin receptor cyclooxygenase inhibitor, a prostaglandin receptor antago agonist, GABA receptor agonist, thrombin receptor antago US 2014/0220079 A1 Aug. 7, 2014 nist, thrombin receptoragonist, opioid receptoragonist, ADP tor antagonist, serotonin receptor agonist, serotonin receptor receptoragonist, leukotriene receptor antagonist, leukotriene antagonist, Vasopressin receptor antagonist, Vasopressin receptor agonist, melatonin receptor agonist, Somatostatin receptor agonist, muscarine receptor antagonist, muscarine receptor agonist, cannabinoid receptor agonist, sphin receptor agonist, adrenalin receptor antagonist, adrenalin gosine-1 phosphate receptoragonist, metabotropic glutamate receptoragonist, angiotensin receptor agonist, GABA recep receptor agonist, phospholipase A2 inhibitor, TGF-beta pro toragonist, thrombin receptor antagonist, thrombin receptor duction inhibitor. Th2 cytokine inhibitor and a combination agonist, opioid receptor agonist, ADP receptor agonist, leu of two or more kinds of them; kotriene receptor antagonist, leukotriene receptor agonist, (50) TLR ligand, cyclic dinucleotide, helper peptide, immu melatonin receptor agonist, somatostatin receptor agonist, nomodulatory Small molecule drug, cyclooxygenase inhibi cannabinoid receptor agonist, sphingosine-1 phosphate tor, prostaglandin receptor antagonist, prostaglandin receptor receptor agonist, metabotropic glutamate receptor agonist, agonist, TSLP production inhibitor, adenylate cyclase inhibi tor, omega-3 fatty acid, PPAR agonist, dopamine receptor phospholipase A2 inhibitor, TGF-beta production inhibitor, antagonist, dopamine receptor agonist, histamine receptor Th2 cytokine inhibitor and a combination of two or more agonist, histamine receptor antagonist, serotonin receptor kinds of them for use in treating or preventing a cancer, agonist, serotonin receptor antagonist, vasopressin receptor wherein the combination is mucosally administered to a Sub antagonist, vasopressin receptor agonist, muscarine receptor ject; and antagonist, muscarine receptor agonist, adrenalin receptor (53) Use of (i) HER2/neu E75 peptide and/or a modified antagonist, adrenalin receptor agonist, angiotensin receptor HER2/neu E75 peptide and (ii) a cellular immunity induction agonist, GABA receptor agonist, thrombin receptor antago promoter selected from TLR ligand, cyclic dinucleotide, nist, thrombin receptoragonist, opioid receptoragonist, ADP helper peptide, immunomodulatory Small molecule drug, receptoragonist, leukotriene receptor antagonist, leukotriene cyclooxygenase inhibitor, prostaglandin receptor antagonist, receptor agonist, melatonin receptor agonist, Somatostatin prostaglandin receptor agonist, TSLP production inhibitor, receptor agonist, cannabinoid receptor agonist, sphin gosine-1 phosphate receptoragonist, metabotropic glutamate adenylate cyclase inhibitor, omega-3 fatty acid, PPAR ago receptor agonist, phospholipase A2 inhibitor, TGF-beta pro nist, dopamine receptor antagonist, dopamine receptor ago duction inhibitor. Th2 cytokine inhibitor, or a combination of nist, histamine receptor agonist, histamine receptor antago two or more kinds of them, for use in promoting the induction nist, serotonin receptor agonist, serotonin receptor of cellular immunity by the mucosal administration of HER2/ antagonist, Vasopressin receptor antagonist, Vasopressin neu E75 peptide and/or a modified HER2/neu E75 peptide; receptor agonist, muscarine receptor antagonist, muscarine (51) A combination of (i) HER2/neu E75 peptide and/or a receptor agonist, adrenalin receptor antagonist, adrenalin modified HER2/neu E75 peptide and (ii) a first cellular receptoragonist, angiotensin receptor agonist, GABA recep immunity induction promoter selected from TLR ligand, toragonist, thrombin receptor antagonist, thrombin receptor cyclic dinucleotide, helper peptide, immunomodulatory agonist, opioid receptor agonist, ADP receptor agonist, leu Small molecule drug, cyclooxygenase inhibitor, prostaglan kotriene receptor antagonist, leukotriene receptor agonist, din receptorantagonist, prostaglandin receptoragonist, TSLP melatonin receptor agonist, somatostatin receptor agonist, production inhibitor, adenylate cyclase inhibitor, omega-3 cannabinoid receptor agonist, sphingosine-1 phosphate fatty acid, PPAR agonist, dopamine receptor antagonist, receptor agonist, metabotropic glutamate receptor agonist, dopamine receptor agonist, histamine receptor agonist, his phospholipase A2 inhibitor, TGF-beta production inhibitor, tamine receptor antagonist, serotonin receptor agonist, sero Th2 cytokine inhibitor, and a combination of two or more tonin receptor antagonist, Vasopressin receptor antagonist, kinds of them, for the manufacture of a cancer vaccine com vasopressin receptor agonist, muscarine receptor antagonist, position for mucosal administration. muscarine receptor agonist, adrenalin receptor antagonist, 0027. Since the cancer vaccine composition of the present adrenalin receptor agonist, angiotensin receptor agonist, invention can be mucosal administered (particularly, nasal GABA receptor agonist, thrombin receptor antagonist, administered and oral, including Sublingual, mucosal admin thrombin receptor agonist, opioid receptor agonist, ADP istered), it has the following advantages: excellent compli receptoragonist, leukotriene receptor antagonist, leukotriene ance, for example, non-invasive administration, no pain, and receptor agonist, melatonin receptor agonist, Somatostatin release from fear of injection; patients can administer the receptor agonist, cannabinoid receptor agonist, sphin cancer vaccine composition by himself/herself since the gosine-1 phosphate receptoragonist, metabotropic glutamate administration is simple; a risk of accidental infection due to receptor agonist, phospholipase A2 inhibitor, TGF-beta pro needlestick injury by health care workers can be avoided; in duction inhibitor. Th2 cytokine inhibitor and a combination the case of repetitive administration, the ambulatory fre of two or more kinds of them, for use in inducing cellular quency can be reduced, and this can contribute to the immunity by the mucosal administration of HER2/neu E75 improvement in quality of life of the patient; and medical peptide and/or a modified HER2/neu E75 peptide; wastes which necessitate special disposition Such as an injec (52) A combination of (i) HER2/neu E75 peptide and/or a tion needle are not generated. Further, there is also an advan modified HER2/neu E75 peptide and (ii) a cellular immunity tage that efficacy of the cancer vaccine composition of the induction promoter selected from TLR ligand, cyclic dinucle present invention is remarkably improved, as compared with otide, helper peptide, immunomodulatory Small molecule the administration of a HER2/neu E75 peptide and/or a modi drug, cyclooxygenase inhibitor, prostaglandin receptor fied HER2/neu E75 peptide alone. Further, the cancer vaccine antagonist, prostaglandin receptor agonist, TSLP production composition of the present invention also has an advantage inhibitor, adenylate cyclase inhibitor, omega-3 fatty acid, that mucosal administration of the composition induce stron PPAR agonist, dopamine receptor antagonist, dopamine ger cellular immunity as compared with injection administra receptoragonist, histamine receptoragonist, histamine recep tion. US 2014/0220079 A1 Aug. 7, 2014

DETAILED DESCRIPTION OF THE INVENTION salt, glutaric acid salt, a variety of amino acid salts etc.), metal 0028 First, terms used in the present specification will be salts (alkali metal salts (e.g. sodium salt, potassium salt), defined so that the present invention can be more easily under alkaline earth metal salts (e.g. calcium salt, magnesium salt), stood. Terms having no definition have the meaning which is aluminum salt etc.), or amine salts (triethylamine salt, ben normally understood by a person skilled in the art in the fields Zylamine salt, diethanolamine salt, t-butylamine salt, dicyclo of particularly, medicine, pharmacy, , cell biol hexylamine salt, arginine salt, dimethylammonium salt, ogy, , polymer chemistry and the like, unless the ammonium salt etc.). A preferable pharmacologically accept context requires otherwise. able salt is an acetic acid salt or a TFA salt. The HER2/neu. E75 peptide and/or the modified HER2/neu E75 peptide I. DEFINITIONS which has been synthesized or produced, isolated and purified 0029. As used herein, the term “HER2/neu E75 peptide' by a well-known method can be used. means a peptide consisting of the sequence: Lys Ile Phe Gly 0034. As used herein, the term “cellular immunity induc Ser Leu Ala Phe Leu (SEQID NO: 1), which is derived from tion promoter” means any substance which can enhance the a product of oncogene HER2/neu (HER2 protein). cellular immune response induced by an antigen which is 0030. As used herein, the term “modified HER2/neu E75 administered together with the Substance, as compared with peptide' means a peptide in which all or a part of amino acids the immune response induced by the antigen without the of the HER2/neu E75 peptide are modified by substitution, Substance. The cellular immunity induction promoter may modification or the like. include Substances specified in the present specification, 0031. The modified HER2/neu E75 peptides includes, for example, though it is not limited by the action mechanism by which (a) a peptide consisting of an amino acid sequence in which induction of the cellular immunity is promoted. one to several, for example, 1, 2, 3, 4 or 5 amino acids are 0035. As used herein, the term “TLR ligand’ means a Substituted, deleted or added in the amino acid sequence of ligand for a Toll-like receptor (TLR), and for example, HER2/neu E75 peptide; and ligands for TLR1 to TLR9 are included. Examples of the TLR (b) a peptide consisting of an amino acid sequence in which ligand include a ligand of a heterodimer of TLR1 and TLR2 all or a part of the amino acids, for example, one or more, for (TLR1/2 ligand), a ligand of a heterodimer of TLR2 and example, 1, 2, 3, 4, 5, 6, 7, 8 or 9 amino acids are modified in TLR6 (TLR2/6 ligand), a TLR2 and Dectin1 ligand, a TLR3 the amino acid sequence of HER2/neu E75 peptide. ligand, a TLR4 ligand, a TLR5 ligand, a TLR7 and/or TLR8 0032 Examples of “modification of an amino acid which ligand, and a TLR9 ligand, all of which can be used as the can be possessed by a modified HER2/neu E75 peptide cellular immunity induction promoter in the present inven include, but not limited to, acetylation; alkylation Such as tion. In a preferred aspect of the present invention, examples methylation; glycosylation, hydroxylation, carboxylation, of the TLR ligand include a TLR1/2 ligand, a TLR3 ligand, a aldehydation, phosphorylation, Sulfonylation, formylation; TLR4 ligand, and a TLR7 and/or TLR8 ligand. aliphatic chain adding modification Such as myristoylation, palmitoylation or Stearoylation; octanoylation, esterification, 0036. As used herein, the term “TLR1/2 ligand’ means a amidation, deamidation; disulfide bond forming modification ligand of a heterodimer of a Toll-like receptor (TLR) 1 and a Such as cystine modification, glutathione modification or Toll-like receptor (TLR) 2, and includes, for example, a tria thioglycolic acid modification; saccharification, ubiquitina cylated lipoprotein derived from a cell wall of a bacterium and tion, Succinimide formation, glutamylation, and prenylation. a salt thereof, and these may be an extract, a product or a The modified HER2/neu E75 peptide may contain substitu synthetic product, and are not limited to them. tion, deletion or addition of one or more amino acids and 0037. In a preferred aspect of the present invention, the modification of one or more amino acids in combination. TLR1/2 ligand is Pam CSK. Pam CSK has the formula:

O Ser-Lys-Lys-Lys-Lys O --~~~~ NH

H3C N-N- 1N--~~~~ 3 O

0033. The HER2/neu E75 peptide and/or the modified 0038. As used herein, the term “TLR2 and Dectin1 ligand” HER2/neu E75 peptide peptide can be in the free form, or any means a ligand of a Toll-like receptor (TLR) 2 and a f1.3- pharmacologically acceptable salt form, for example, a form glucan receptor (Dectin1), and includes, for example, a B1.3- of acid salts (acetic acid salt, TFA salt, hydrochloric acid salt, glucan derived from a cell wall of a fungus and a salt thereof, Sulfuric acid salt, phosphoric acid salt, lactic acid salt, tartaric and these may be an extract, a product or a synthetic product, acid salt, maleic acid salt, fumaric acid salt, oxalic acid salt, and are not limited to them. In a preferable aspect of the hydrobromic acid salt, Succinic acid salt, nitric acid salt, present invention, the TLR2 and Dectin1 ligand is Zymosan malic acid salt, citric acid salt, oleic acid salt, palmitic acid derived from a yeast cell wall. salt, propionic acid salt, formic acid salt, benzoic acid salt, 0039. As used herein, the term “TLR3 ligand’ means a picric acid salt, benzenesulfonic acid salt, dodecylsulfuric ligand of a Toll-like receptor (TLR) 3, and includes, for acid salt, methanesulfonic acid salt, p-toluenesulfonic acid example, a double-stranded RNA (dsRNA) derived from a US 2014/0220079 A1 Aug. 7, 2014

virus and a salt thereof, and these may be an extract, a product or a synthetic product, and are not limited to them. In a NH2 preferable aspect of the present invention, the TLR3 ligand is polyinosinic-polycytidylic acid (Poly(I:C)) which is a syn N 21 \ thetic product and/or a salt thereof. 0040. As used herein, the term “TLR4 ligand’ means a X ligand of a Toll-like receptor (TLR) 4, and includes, for N O example, a lipopolysaccharide (LPS) derived from a bacte \ rium or a plant, particularly, a lipid A derivative, for example, monophosphoryl lipid A, a 3 deacylated monophosphoryl lipid A (3D-MPL), OM174, OM 294 DP or OM. 197 MP-Ac OH DP and the like, alkyl glucosaminide phosphate (AGP), for example, AGP disclosed in WO 98/50399 or U.S. Pat. No. 6,303,347, or a salt of AGP as disclosed in U.S. Pat. No. 0045. In another preferred aspect, the TLR7 and/or TLR8 6,764,840, and a lipopolysaccharide derived from a Pantoea ligand is TLR7-II. TLR7-II is represented by the formula: bacterium, a glucopyranosyl lipid, and Sodium hyaluronate, but is not limited to them. 0041. In a preferable aspect of the present invention, as the NH TLR4 ligand, lipopolysaccharides derived from genus Aceto 2 N bacter (e.g. Acetobacter aceti, Acetobacter xylinum, Aceto N bacter Orientalis etc.), genus Zymomonas (e.g. Zymomonas Sa mobilis etc.), genus Xanthomonas (e.g. Xanthomonas O JJ)N N or campestris etc.), genus Enterobacter (e.g. Enterobacter cloa Cae etc.), and genus Pantoea (e.g. Pantoea agglomerans etc.) are preferable. Extracts derived from these lipopolysaccha rides or purified lipopolysaccharides can be used as they are. In addition, for example, lipopolysaccharides (IP-PA1) -O derived from Pantoea agglomerans can be purchased from Funakoshi Corporation. In addition, in a preferable aspect of the present invention, the TLR4 ligand is a lipopolysaccha 0046. In another preferred aspect, the TLR7 and/or TLR8 ride derived from a Pantoea bacterium, glucopyranosyl lipid, ligand is bropirimine. Bropirimine is represented by the for and/or sodium hyaluronate. mula: 0042. As used herein, the term “TLR7 and/or TLR8 ligand means a ligand of a Toll-like receptor (TLR) 7 and/or TLR8, and includes, for example, a single-stranded RNA, imiquimod, residuimod (R848), TLR7-II and other com pounds, for example, loxoribine and bropirimine, but is not Br limited to them. 0043. In a preferable aspect of the present invention, the ll. N NH TLR7 and/or TLR8 ligand is imiquimod. Imiquimod is 1-(2- H 2 methylpropyl)-1H-imidazo[4,5-cquinoline-4-amine of the formula:

0047. As used herein, the term “TLR9 ligand’ means a ligand of a Toll-like receptor (TLR) 9, and includes, for example, ODN1826 and the like. The TLR9 ligand used in the present invention may be an extract, a product or a synthetic product, and is not limited to them. In a preferable aspect of the present invention, the TLR9 ligand is ODN1826. 0048 ODN1826 is an oligodeoxynucleotide consisting of the following sequence (SEQID NO: 2):

5'-tccatgacgttcctgacgtt-3' 0049. As used herein, the term “TLR2/6 ligand’ means a ligand of a heterodimer of Toll-like receptor (TLR) 2 and a and, for example, the characteristics and a production process Toll-like receptor (TLR) 6, and includes, for example, a dia thereofare described in JP 7-505883 A (Patent Document 4). cylated lipoprotein derived from a cell wall of mycoplasma 0044) In another preferred aspect, the TLR7 and/or TLR8 and a salt thereof, and these may be an extract, a product or a ligand is residuimod. Residuimod is 4-amino-2-(ethoxym synthetic product, and are not limited to them. In a preferable ethyl)-O.C.-dimethyl-1H-imidazo 4.5-c quinolin-1-ethanol aspect of the present invention, the TLR2/6 ligand is of the formula: Pam CSK, MALP-2 and/or FSL-1. US 2014/0220079 A1 Aug. 7, 2014 10

0050 Pam CSK is represented by the following formula:

O Ser-Lys-Lys-Lys-Lys O

HC ~~~~ NH2 HC N-N- S

O

0051. FSL-1 is represented by the following formula: CH3(CH2)4 NY O O NH2 ls S Gly-Asp-Pro-Lys-His-Pro-Lys-Ser-Phe CH3(CH2)4 O O

0052. As used herein, the term “TLR5 ligand’ means a CD80, and CD86, a major histocompatibility complex mol ligand of a Toll-like receptor (TLR) 5, and includes, for ecule, and a chemokine receptor. Type I interferons (IFNC. example, flagellin and the like. The TLR5 ligand used in the and IFNB) are produced by a cell upon activation with TLR7 present invention may be an extract, a product or a synthetic and/or TLR8 agonists. 0054 As used herein, the term “cyclic dinucleotide' product, and is not limited to them. In a preferable aspect of means a molecule in which two OH groups of a Sugar part of the present invention, the TLR5 ligand is flagellin. two nucleotides produce an ester for each same phosphoric 0053. The Toll-like receptor (TLR) is a family of type I acid molecule, and thereby nucleotides are cyclized, and an transmembrane proteins which initiates congenital immune analog thereof, and includes, for example, cyclic di-AMP response in which a specific cytokine, a specific chemokine (c-di-AMP), cyclic di-GMP (c-di-GMP). c-dGpGp, c-dCip and a growth factor participate, by in vivo activation thereof. dGp, c-GpAp, c-GpCp, c-GpUp and the like, but is not lim All TLRs can activate a certain intracellular signal transmis ited to them. The cyclic dinucleotide activates a dendritic cell sion molecule, for example, a nuclearity factor KB (NF-kB) or a T cell. Further examples of the cyclic dinucleotide, use of and a mitogen-activated protein kinase (MAP kinase) or the them as an adjuvant, and a process for producing them are like, while a specific population of a cytokine and a chemok described in JP 2007-529531 A (Patent Document 5). In a ine which are released seems to be inherent to each TLR. preferable aspect of the present invention, the cyclic dinucle TLR1/2, TLR2/6, TLR4 and TLR5 are widely expressed in otide is cyclic di-GMP and/or cyclic di-AMP. The cyclic immune cells (dendritic cells, monocytes and the like) as well di-GMP has the formula: as general cells such as mucosal epithelial cells. It is known that these receptors recognize the constituent components of bacteria and promote the secretion of inflammatory cytokines (TNF-C., IL-1 and IL-6). In addition, it is known that TLR4 further promotes a production of type I interferons (IFNC. and IFNB). TLR3,7,8 and 9 include a subfamily of TLR which is present in an endosome fraction or a lysosome fraction of an immune cell (e.g. dendritic cell and monocyte). Specifically, TLR3 is expressed by a wide range of cells such as a dendritic cell and a fibroblast, TLR7 is expressed by a plasma cell-like dendritic cell, and is expressed by a monocyte to a lesser extent, TLR8 is expressed by a monocyte as well as a mono cyte-derived dendritic cell and a myeloid dendritic cell, and TLR9 is expressed by a plasma cell-like dendritic cell. This Subfamily mediates recognition of a microorganism nucleic acid (single-stranded RNA, double-stranded RNA, single and a process for synthesizing it is described in Kawai et al., stranded DNA etc.). Agonists of TLR3, TLR7 and/or TLR8, Nucleic Acids Research Suppl. 3: 103-4. and TLR9 stimulate production of a variety of inflammatory 0055 As used herein, the term “helperpeptide' means any cytokines, for example, interleukin-6, interleukin-12, TNF peptide which activates helper T cells, including, for C., and interferon-Y. Such agonists also promote increase in example, a helper peptide derived from tuberculosis, a helper expression of a costimulatory molecule, for example, CD40, peptide derived from measles virus, a helper peptide derived US 2014/0220079 A1 Aug. 7, 2014

from Hepatitis B virus, a helperpeptide derived from hepatitis coxib, Valdecoxib, parecoxib, lumiracoxib, meloxicam, C virus, a helper peptide derived from Chlamydia trachoma tenoxicam, diclofenac, mefenamic acid, tolfenamic acid, tis, a helper peptide derived from Pfalciparum sporozoite, a flufenamic acid, meclofenamic acid, niflumic acid, benzy helper peptide derived from keyhole limpet haemocyanin, a damine, indobufen, triflusal, tolmetin, fenoprofen, tiapro helper peptide derived from tetanus toxin, a helper peptide fenic acid, felbinac, nepafenac, amfenac, pravadoline, Zalto derived from pertussis toxin, a helper peptide derived from profen, Sulindac, nabumetone, diflunisal, piroxicam, diphtheria toxin, a helper peptide derived from cancer cell ibuprofen, naproxen, fenoprofen, aspirin, methyl salicylate, (for example, an IMA-MMP-001 helper peptide, a CEA-006 salicylamide, Salsalate, aloxiprin, tolmetin, indomethacin, helper peptide, an MMP-001 helper peptide, a TGFBI-004 proglumetacine, acemetacin, flurbiprofen, pranoprofen, helper peptide, an HER-2/neu (aa776-790) helper peptide, an acetaminophen, floctafenine, lornoxicam, tenoxicam, tiapro AE36 helper peptide, an AE37 helper peptide, an MET-005 fenic acid, oxaprozin, ketoprofen, dexketoprofen, dexibupro helper peptide, a BIR-002 helper peptide), and universal fen, alminoprofen, ketorolac, mofeZolac, phenylbutaZone, helper analogs (for example, PADRE). In a preferable aspect oxyphenylbutaZone, ketophenylbutaZone, feprazone, phenb of the present invention, the helper peptide consists of 10 to utaZone, ethenZamide, tiaramide, tinoridine, epirizole, emor 18 amino acids, preferably 12 to 16 amino acids, more pref faZone and a derivative thereof, as well as a pharmacologi erably 13 to 15 amino acids. In a preferred aspect of the cally acceptable salt thereof. In a preferable aspect of the present invention, the helperpeptide is Peptide-25 or PADRE. present invention, the COX inhibitor is etodolac and/or loxo Peptide-25 is a peptide of 15 amino acids consisting of a profen. sequence Phe Gln Asp Ala Tyr Asn Ala Gly His Asn Ala Val Phe (SEQID NO:3), the sequence corresponds to the amino 0060 Loxoprofen is represented by the formula: acid residue 240-254 of Ag85B, the major protein secreted by human-type tuberculosis (Mycobacterium tuberculosis). PADRE is a peptide of 13 amino acids consisting of a sequence D-Ala Lys cyclohexyl-Ala Val Ala Trp Thr Leu Lys O OH . Ala D-Ala (Herein referred as SEQID NO: 4). 0056 Further, in the invention, instead of the helper pep tide, or in combination of the helper peptide, any peptide O modified by substitution or modification of all or some amino acids of the helper peptide (hereinafter referred as “modified helper peptide') can also be used. 0061. As used herein, the term “prostaglandin receptor 0057 The modified helper peptide includes, for example, antagonist’ means a Substance having the function of pre (a) a peptide consisting of an amino acid sequence in which venting prostaglandin from acting on a receptor, and includes, one to several, for example, one, two, three, four or five amino for example, an EP2 receptor antagonist, an EP4 receptor acids are substituted, deleted or added, in an amino acid antagonist, a DP receptor antagonist, and an IP receptor sequence of the original helper peptide; and antagonist. (b) a peptide consisting of an amino acid sequence in which 0062. As used herein, the term “EP2 receptor antagonist' all or apart of amino acids, for example, one or more, for means a Substance having the function of preventing prostag example, one, two, three, four, five, six, seven, eight, nine, landin E2 from acting on an EP2 receptor. Examples of the ten, eleven, twelve, thirteen, fourteen, or fifteen amino acids EP2 receptor antagonist include AH6809 and a derivative are modified, in an amino acid sequence of the original helper thereof, as well as a pharmacologically acceptable salt peptide. thereof. 0058 Examples of the “modification of an amino acid which can be possessed by the modified helper peptide 0063 AH6809 is represented by the formula: include, but are not limited to, aliphatic chain addition modi fication Such as acetylation, alkylation Such as methylation, glycosylation, hydroxylation, carboxylation, aldehydization, phosphorylation, Sulfonylation, formylation, addition offatty acid such as myristoylation, palmitoylation and Stearoylation, O octanoylation, esterification, amidation, deamidation, disul COOH . fide bond formation modification Such as cystine modifica tion, glutathione modification and thioglycolic acid modifi cation, glycation, ubiquitination, Succinimide formation glutamylation, prenylation and the like. In addition, the modi 1. O fied helperpeptide may contain a combination of substitution, deletion or addition of one or more amino acids, and modifi cation of one or more amino acids. 0059. As used herein, the term “cyclooxygenase inhibi tor” means a substance which inhibits the function of cyclooxygenase (COX). This is also referred to as “COX 0064. As used herein, the term “EP4 receptor antagonist' inhibitor hereinafter. As COX inhibitors, there are a COX means a Substance having the function of preventing prostag inhibitor which selectively acts on particular cyclooxygenase landin E2 from acting on an EP4 receptor. Examples of the (e.g. COX-1 or COX-2), and a COX inhibitor having no EP4 receptor antagonist include GW627368X and a deriva selectivity. Examples of COX inhibitors which can be used in tive thereof, as well as a pharmacologically acceptable salt the present invention include etodolac, loxoprofen, cele thereof. US 2014/0220079 A1 Aug. 7, 2014 12

0065 GW627368X is represented by the formula: 0072 Sulprostone is represented by the formula:

- O

N Q O O \/ O N1

(0073. As used herein, the term “TSLP production inhibi tor” means a Substance having the function of inhibiting 0066. As used herein, the term “DP receptor antagonist' production of TSLP. Since a drug which inhibits NF-kB is means a Substance having the function of preventing prostag thought to indirectly inhibit the production of TSLP, it is landin D. from acting on a DP receptor. Examples of the DP included in this category. Examples of the TSLP production receptor antagonist include S-5751, BWA868C and a deriva inhibitor include naringenin, berberine, resveratrol, luteolin, tive thereof, as well as a pharmacologically acceptable salt apigenin, chrysoeriol, Velutin, rutin, hesperidin, quercetin, thereof. daidzein, genistein, noscapine, diindolylmethane, Xanthone, parthenolide and a derivative thereof, as well as a pharmaco 0067 BWA868C is represented by the formula: logically acceptable salt thereof. (0074 Berberine is represented by the formula: O OH

O HO N1 O Y. (ICOO n OCH

OCH

0068. As used herein, the term “IP receptor antagonist' 0075. As used herein, the term “adenylate cyclase inhibi means a Substance having the function of preventing prostag tor” means a Substance having the function of inhibiting the landin I from acting on an IP receptor. Examples of the IP activity of adenylate cyclase. Examples of the adenylate receptor antagonist include RO11384.52 and a derivative cyclase inhibitor include 2',5'-dideoxyadenosine, niacin, thereof, as well as a pharmacologically acceptable salt insulin, and a derivative thereof, as well as a pharmacologi thereof. cally acceptable salt thereof. 0069 RO1138452 is represented by the formula: 0076 2.5'-Dideoxyadenosine is represented by the for mula:

NH2

N n N. CO {lN % O 0070. As used herein, the term"prostaglandin receptor agonist’ means a Substance having the function of acting on a prostaglandin receptor, and includes, for example, an EP3 oH receptor agonist. (0071. As used herein, the term “EP3 receptor agonist” 0077. As used herein, the term “omega-3 fatty acid refers means a Substance having the function of acting on an EP3 to an unsaturated fatty acid having a carbon-carbon double receptor. Examples of the EP3 receptor agonist include sul bond at the co-3 position. Examples of the omega-3 fatty acid prostone, GR63799, cloprostenol, ONO-AE-248, carbacy include eicosapentaenoic acid, C-linolenic acid, docosa clin, and a derivative thereof, as well as a pharmacologically hexaenoic acid, and a derivative thereof, as well as a pharma acceptable salt thereof. cologically acceptable salt thereof. US 2014/0220079 A1 Aug. 7, 2014

0078 Eicosapentaenoic acid is represented by the for I0084 Benzazepine is represented by the formula: mula:

\

le

I0085. As used herein, the term “D5 receptor antagonist' means a Substance having the function of preventing dopam ine from acting on a D5 receptor. Examples of the D5 receptor antagonist include SCH39166 and a derivative thereof, as well as a pharmacologically acceptable salt thereof. I0086 SCH39166 is represented by the formula: 0079. As used herein, the term “PPAR agonist” means a Substance having the function of acting on a peroxisome proliferator-activated receptor, and includes, for example, a PPAR-O. agonist, a PPAR-8 agonist, and a PPAR-Yagonist. 0080. As used herein, the term “PPAR-O. agonist’ means a Substance having the function of acting on an C. type peroxi some proliferator-activated receptor. The term “PPAR-8 ago nist’ means a substance having the function of acting on a Ö type peroxisome proliferator-activated receptor. The term “PPAR-Yagonist’ means a substance having the function of acting on a Y type peroxisome proliferator-activated receptor. Examples of the PPAR-O. agonist, and/or the PPAR-8 agonist, and/or the PPAR-Y agonist include clofibrate, fenofibrate, bezafibrate, ciprofibrate, etofibrate, telmisartan, oleylethano I0087 As used herein, the term "dopamine receptor ago lamide, tetradecylthioacetic acid, troglitaZone, pioglitaZone, nist’ means a Substance having the function of acting on a rosiglitaZone, balaglitaZone, rivoglitaZone, ciglitaZone, dar dopamine receptor, and includes, for example, a D2 receptor glitaZone, edaglitaZone, netoglitaZone, indeglitazar, tesagli agonist, a D3 receptor agonist, and a D4 receptor agonist. tazar, muraglitazar, aleglitazar, and a derivative thereof, as I0088 As used herein, the term “D2 receptor agonist' well as a pharmacologically acceptable salt thereof. means a Substance having the function of acting on a D2 receptor. Examples of the D2 receptoragonist include caber I0081) Clofibrate is represented by the formula: goline, bromocriptine, pergolide, ropinirole, talipexole, arip iprazole, lurasidone, and a derivative thereof, as well as a pharmacologically acceptable salt thereof. I0089 Ropinirole is represented by the formula:

N r C

O. N 0082. As used herein, the term "dopamine receptor H antagonist means a Substance having the function of pre venting dopamine from acting on a receptor, and includes, for example, a D1 receptor antagonist, and a D5 receptor antago nist. 0083. As used herein, the term “D1 receptor antagonist' 0090. As used herein, the term “D3 receptor agonist' means a Substance having the function of preventing dopam means a Substance having the function of acting on a D3 ine from acting on a D1 receptor. Examples of the D1 receptor receptor. Examples of the D3 receptoragonist include piribe antagonist include benzazepine, fenoldopam, lorcaserin, dil, rotigotine, PD1289077, OH-DPAT and a derivative SCH23390, SCH39166, LE300 and a derivative thereof, as thereof, as well as a pharmacologically acceptable salt well as a pharmacologically acceptable salt thereof. thereof. US 2014/0220079 A1 Aug. 7, 2014 14

0091 Rotigotine is represented by the formula: 0096 Diphenhydramine is represented by the formula:

0097. As used herein, the term “H2 receptor antagonist' means a Substance having the function of preventing hista 0092. As used herein, the term “D4 receptor agonist' mine from acting on a H2 receptor. Examples of the H2 receptor antagonist include cimetidine, ranitidine, famoti means a Substance having the function of acting on a D4 dine, nizatidine, roXatidine, lafutidine, and a derivative receptor. Examples of the D4 receptor agonist include fli thereof, as well as a pharmacologically acceptable salt banserin, ABT724, PD168077, CP226269 and a derivative thereof. thereof, as well as a pharmacologically acceptable salt 0.098 Famotidine is represented by the formula: thereof.

0093. Flibanserin is represented by the formula: S N -{ re- N S n HN 4. CF3. His/ \ / \ / YNH. \ / 0099. As used herein, the term “histamine receptor ago nist’ means a Substance having the function of acting on a histamine receptor, and includes, for example, a H1 receptor agonist, a H3 receptor agonist, and a H4 receptor agonist. 0100. As used herein, the term “H1 receptor agonist' means a Substance having the function of acting on a H1 receptor. Examples of the H1 receptor agonist include 2-py ridylethylamine, 2-thiazolylethylamine and a derivative 0094. As used herein, the term “histamine receptor thereof, as well as a pharmacologically acceptable salt antagonist means a Substance having the function of pre thereof. venting histamine from acting on a receptor, and includes, for 0101 2-Pyridylethylamine is represented by the formula: example, a H1 receptor antagonist, and a H2 receptor antago nist. N NH2. 0095. As used herein, the term “H1 receptor antagonist' n means a Substance having the function of preventing hista mine from acting on a H1 receptor. Examples of the H1 2 receptor antagonist include ketanserin, thonzylamine, mepyramine, tripelenamine, dimethindene, clemastine, 0102. As used herein, the term “H3 receptor agonist' bamipine, isothipendyl, chlorphenoxamine, dimetotiazine, means a Substance having the function of acting on a H3 chlorpromazine, hydroxy Zine, opipramol, betahistine, cin receptor. Examples of the H3 receptor agonist include narizine, levocabastine, antazoline, diphenylpyraline, carbi immethridine, imetit, immepip, C.-methylhistamine, proxy noxamine, doxylamine, alimemazine, cyclizine, meclozine, fan, and a derivative thereof, as well as a pharmacologically levocetirizine, cyproheptadine, phenindamine, triprolidine, acceptable salt thereof. aZatadine, astemizole, terfenadine, acrivastine, ebastine, 0103 Proxyfan is represented by the formula: desloratadine, rupatadine, bilastine, mizolastine, noberas tine, rocastine, temelastine, bepotastine, diphenhydramine, chlorpheniramine, ketotifen, promethazine, cyproheptadine, epinastine, olopatadine, bepotastine, astemizole, emedastine, meduitazine, Oxatomide, loratadine, fexofenadine, cetirizine, aZelastine, and a derivative thereof, as well as a pharmaco logically acceptable salt thereof. US 2014/0220079 A1 Aug. 7, 2014

0104. As used herein, the term “H4 receptor agonist' 0111. As used herein, the term “5-HT6 receptor antago means a Substance having the function of acting on a H4 nist’ means a Substance having the function of preventing receptor. Examples of the H4 receptoragonist include 4-me serotonin from acting on a 5-HT6 receptor. Examples of the thylhistamine, VUF8430, immepip and a derivative thereof, 5-HT6 receptor antagonist include cerlapirdine, clozapine as well as a pharmacologically acceptable salt thereof. and a derivative thereof, as well as a pharmacologically 0105 4-Methylhistamine is represented by the formula: acceptable salt thereof. 0112 Cerlapirdine is represented by the formula:

N NH2. H N ( N N HC M N H 3- N N 1S-1N OS 0106. As used herein, the term "serotonin receptor antago CH3 V nist’ means a Substance having the function of preventing serotonin from acting on a receptor, and includes, for example, a 5-HT2 receptor antagonist, a 5-HT4 receptor antagonist, a 5-HT6 receptor antagonist, and a 5-HT7 recep tor antagonist. 0107 As used herein, the term “5-HT2 receptor antago 0113. As used herein, the term “5-HT7 receptor antago nist’ means a Substance having the function of preventing nist’ means a Substance having the function of preventing serotonin from acting on a 5-HT2 receptor. Examples of the serotonin from acting on a 5-HT7 receptor. Examples of the 5-HT2 receptor antagonist include pizotifen, risperidone, 5-HT7 receptor antagonist include lurasidone, metergoline, olanzapine, quetiapine, aripiprazole, blonanserin, clozapine, and a derivative thereof, as well as a pharmacologically paliperidone, ritanserin, yohimbine, mesulergine, ago acceptable salt thereof. melatine, cyclobenzaprine, Sarpogrelate, methysergide, ket 0114 Metergoline is represented by the formula: anserin, and a derivative thereof, as well as a pharmacologi cally acceptable salt thereof. 0108 Olanzapine is represented by the formula:

cN ) N

N S

0109 As used herein, the term “5-HT4 receptor antago 0.115. As used herein, the term "serotonin receptor ago nist’ means a Substance having the function of preventing nist’ means a Substance having the function of acting on a serotonin from acting on a 5-HT4 receptor. Examples of the serotonin receptor, and includes, for example, a 5-HT1 recep 5-HT4 receptor antagonist include piboserod, GR113808, toragonist, and a 5-HT2 receptor agonist. GR125487, RS39604, SB204070 and a derivative thereof, as 0116. As used herein, the term “5-HT1 receptor agonist' well as a pharmacologically acceptable salt thereof. means a Substance having the function of acting on a 5-HT1 receptor. Examples of the 5-HT1 receptor agonist include 0110 Piboserod is represented by the formula: picloZotan, tandospirone, Sumatriptan, Zolmitriptan, eletrip tan, rizatriptan, naratriptan, almotriptan, froVatriptan, avitrip tan, ergotamine, ergot alkaloid, and a derivative thereof, as well as a pharmacologically acceptable salt thereof. 0117 Zolmitriptan is represented by the formula:

H O={N V co O US 2014/0220079 A1 Aug. 7, 2014

0118. As used herein, the term “5-HT2 receptor agonist' receptor antagonist include tolvaptan, moZavaptan, conivap means a Substance having the function of acting on a 5-HT2 tan, lixivaptan, and a derivative thereof, as well as a pharma receptor. Examples of the 5-HT2 receptor agonist include cologically acceptable salt thereof. C.-methyl-5-HT, agomelatine, norfenfluramine, meta-chlo 0.122 Mozavaptain is represented by the formula: rophenylpiperazine and a derivative thereof, as well as a pharmacologically acceptable salt thereof. 0119 Agomelatine is represented by the formula: O

O N O N 1s H H - I0123. As used herein, the term “vasopressin receptor ago 1. O nist’ means a Substance having the function of acting on a vasopressin receptor, and includes, for example, a V1 recep toragonist. 0120. As used herein, the term “vasopressin receptor 0.124. As used herein, the term “V1 receptor agonist 99 antagonist means a Substance having the function of pre means a Substance having the function of acting on a V1 venting vasopressin from acting on a receptor, and includes, receptor. Examples of the V1 receptor agonist include vaso for example, a V2 receptor antagonist. pressin, fely pressin, desmopressin, lypressin, terlipressin, 0121. As used herein, the term “V2 receptor antagonist' ornipressin, argipressin, and a derivative thereof, as well as a means a Substance having the function of preventing vaso pharmacologically acceptable salt thereof. pressin from acting on a V2 receptor. Examples of the V2 0.125 Desmopressin is represented by the formula:

O NH2 n

'n NH2 O HN O NH2 21

O O O NH n N 21 O n HN HN N ne's NH2.

HO

I0126. As used herein, the term “muscarine receptor antagonist’ means a Substance having the function of pre venting acetylcholine from acting on a muscarine receptor, and includes, for example, a M1 receptor antagonist, a M3 receptor antagonist, and a M5 receptor antagonist. I0127. As used herein, the term “M1 receptor antagonist' means a Substance having the function of preventing acetyl choline from acting on a M1 receptor. The term “M3 receptor antagonist’ means a Substance having the function of pre venting acetylcholine from acting on a M3 receptor. The term “M5 receptor antagonist’ means a Substance having the func tion of preventing acetylcholine from acting on a M5 receptor. Examples of the M1 receptor antagonist, and/or the M3 receptor antagonist, and/or the M5 receptor antagonist include pirenzepine, atropine, trimebutine, piperidolate, oxy butynin, tropicamide, propiverine, tolterodine, Solifenacin, US 2014/0220079 A1 Aug. 7, 2014 darifenacin, imidafenacin, oxyphencyclimine, tiotropium I0135. As used herein, the term “B1 receptor antagonist' bromide, esoxybutynin, tiquizium, and a derivative thereof, means a Substance having the function of preventing adrena as well as a pharmacologically acceptable salt thereof. lin from acting on a B1 receptor. The term “B2 receptor 0128 Oxybutynin is represented by the formula: antagonist’ means a Substance having the function of pre venting adrenalin from acting on a B2 receptor. The term “B3 receptor antagonist’ means a Substance having the function of preventing adrenalin from acting on a B3 receptor. Examples of the B1 receptor antagonist, and/or the B2 recep OH 1n tor antagonist, and/or the B3 receptor antagonist include N bopindolol, pindolol, timolol, dichloroisoprenaline, alpre nolol, carteolol, indenolol, bunitrolol, penbutolol, propra oue1 N nolol, nadolol, nipradilol, tilisolol, acebutolol, celiprolol, O metoprolol, atenolol, bisoprolol, betaxolol, practolol, bevan tolol, butoxamine, carvedilol, amoSulalol, arotinolol, labe talol, and a derivative thereof, as well as a pharmacologically 0129. As used herein, the term “muscarine receptor ago acceptable salt thereof. nist’ means a Substance having the function of acting on a 0.136 Propranolol is represented by the formula: muscarine receptor, and includes, for example, a M1 receptor agonist, a M2 receptor agonist, a M3 receptor agonist, a M4 receptor agonist, and a M5 receptor agonist. 0130. As used herein, the term “M1 receptor agonist' means a Substance having the function of acting on a M1 receptor. The term “M2 receptor agonist’ means a substance H having the function of acting on a M2 receptor. The term “M3 O~~ N 1. receptor agonist’ means a Substance having the function of OH acting on a M3 receptor. The term “M4 receptor agonist' means a Substance having the function of acting on a M4 0.137 As used herein, the term “angiotensin receptor ago receptor. The term “M5 receptor agonist’ means a substance nist’ means a Substance having the function of acting on an having the function of acting on a M5 receptor. Examples of angiotensin receptor, and includes, for example, an AT2 the M1 receptor agonist, and/or the M2 receptor agonist, receptor agonist. and/or the M3 receptor agonist, and/or the M4 receptor ago 0.138. As used herein, the term “adrenalin receptor ago nist, and/or the M5 receptor agonist include acetylcholine, nist’ means a Substance having the function of acting on an aceclidine, alvameline, talsaclidine, Xanomeline, pilocarpine, adrenalin receptor, and includes, for example, an O.1 receptor cevimeline, bethanechol, maZaticol, muscarine, and a deriva agonist, and an O2 receptor agonist. tive thereof, as well as a pharmacologically acceptable salt 0.139. As used herein, the term "C.1 receptor agonist' thereof. means a Substance having the function of acting on an C.1 0131 Bethanechol is represented by the formula: receptor. The term “O2 receptor agonist’ means a Substance O having the function of acting on an O2 receptor. Examples of the C.1 receptor agonist, and/or the O2 receptor agonist 1. O NH2. include norepinephrine, norfenefrine, etillefrine, naphazoline, phenylephrine, midodrine, methoxamine, oxedrine, met 0.132. As used herein, the term “adrenalin receptor antago araminol, arbutamine, ephedrine, oxymetazoline, tetry Zoline, nist’ means a Substance having the function of preventing Xylometazoline, tramaZoline, pseudoephedrine, diplivefrine, adrenalin from acting on a receptor, and includes, for amidephrine, methylephedrine, rillmenidine, brimonidine, example, an O.1 receptor antagonist, a B1 receptor antagonist, medetomidine, Xylazine, tizanidine, guanfacine, methyldopa, a B2 receptor antagonist, and a B3 receptor antagonist. guanabenz, and a derivative thereof, as well as a pharmaco 0133. As used herein, the term “C.1 receptor antagonist' logically acceptable salt thereof. means a Substance having the function of preventing adrena 0140 Xylazine is represented by the formula: lin from acting on an O.1 receptor. Examples of the C.1 recep tor antagonist include prazosin, doxazosin, bunaZosin, trima Zosin, alfuZosin, silodosin, teraZosin, tamusulosin, and a derivative thereof, as well as a pharmacologically acceptable salt thereof. 0134 Tamsulosin is represented by the formula: 1. H3C CH3

O O HN1\/ n1nO H HC O 0141 AS used herein, the term “angiotensin receptor ago HCO 3 in 1 nist’ means a Substance having the function of acting on an angiotensin receptor, and includes, for example, an AT2 receptor agonist. US 2014/0220079 A1 Aug. 7, 2014

0142. As used herein, the term “AT2 receptor agonist' 0149 Vorapaxar is represented by the formula: means a Substance having the function of acting on an AT2 receptor. Examples of the AT2 receptoragonist include novo kinin, angiotensin and a derivative thereof, as well as a phar macologically acceptable salt thereof. 0143 Angiotensin is represented by the formula:

0150. As used herein, the term “thrombin receptor ago nist’ means a Substance having the function of acting on a thrombin receptor, and includes, for example, a PAR-1 recep 0144) As used herein, the term “GABA receptor agonist' toragonist. means a Substance having the function of acting on a GABA 0151. As used herein, the term “PAR-1 receptor agonist' receptor, and includes, for example, a GABA receptor ago means a Substance having the function of acting on a PAR-1 nist. receptor. Examples of the PAR-1 receptor agonist include TRAP-6, TRAP-14, NAT6-NH and a derivative thereof, as (0145 As used herein, the term "GABA receptoragonist” well as a pharmacologically acceptable salt thereof. means a Substance having the function of acting on a GABA receptor. Examples of the GABA receptor agonist include 0152 TRAP-6 is represented by the formula: baclofen, y-aminobutyric acid, arbaclofen and a derivative thereof, as well as a pharmacologically acceptable salt thereof. 0146 Baclofen is represented by the formula: O

HN O O O NH2. O HN OH 2-Y/, N , N l, N H H H OH. O O O OH

C NH ins NH2

0147 As used herein, the term “thrombin receptor antago nist’ means a Substance having the function of preventing thrombin from acting on a receptor, and includes, for 0153. As used herein, the term “opioid receptor agonist' example, a PAR-1 receptor antagonist. means a Substance having the function of acting on an opioid receptor. 0148. As used herein, the term “PAR-1 receptor antago 0154 Examples of the opioid receptor agonist include nist’ means a Substance having the function of preventing trimebutine, alvimopan, morphine, oxycodone, dihydroco thrombin from acting on a PAR-1 receptor. Examples of the deine, diamorphine, pethidine, pentazocine, buprenorphine, PAR-1 receptor antagonist include Vorapaxar, atopaxar, butorphanol, nalbuphine, tilidine, dezocine, meptazinol, tap FR171113, RW,7561 10, dabigatran, dabigatran etexilate, entadol, naltrexone, methadone, ethylmorphine, hydroc melagatran, Ximelagatran, hirudin, hirulog, argatroban and a odone, acetyldihydrocodeine, nalorphine, loperamide, derivative thereof, as well as a pharmacologically acceptable remoxipride, opipramol, and a derivative thereof, as well as a salt thereof. pharmacologically acceptable salt thereof. US 2014/0220079 A1 Aug. 7, 2014 19

0155 Buprenorphine is represented by the formula: 0162. As used herein, the term “ADP receptor agonist' means a Substance having the function of acting on an ADP receptor. Examples of the ADP receptor agonist include adenosine diphosphate, and a derivative thereof, as well as a pharmaco logically acceptable salt thereof. 0163 Adenosine diphosphate is represented by the for mula:

HN HO OCH sN 0156. As used herein, the term “leukotriene receptor O O antagonist means a Substance having the function of pre HO-P-O-P-O C 2. venting leukotriene from acting on a receptor, and includes, for example, a CysLT1 receptor antagonist, and a CysLT2 O O receptor antagonist. 0157. As used herein, the term “CysLT1 receptor antago nist’ means a Substance having the function of preventing OH OH leukotriene from acting on a CysLT1 receptor. The term “CySLT2 receptor antagonist’ means a Substance having the 0164. As used herein, the term “melatonin receptor ago function of preventing leukotriene from acting on a CysLT2 nist’ means a Substance having the function of acting on a receptor. Examples of the CysLT1 receptorantagonist, and/or melatonin receptor. Examples of the melatonin receptor ago the CySLT2 receptor antagonist include montelukast, nist include melatonin, perlapine, tasimelteon, and a deriva Zafirlukast, pranlukast, and a derivative thereof, as well as a tive thereof, as well as a pharmacologically acceptable salt pharmacologically acceptable salt thereof. Examples of the thereof. pharmacologically acceptable salt of montelukast include 0.165 Melatonin is represented by the formula: montelukast sodium and the like. 0158 Montelukast sodium is represented by the formula: H3CNo

HN CH3. HN r O

0166 As used herein, the term “somatostatin receptor agonist means a Substance having the function of acting on a Somatostatin receptor. Examples of the Somatostatin receptor agonist include Somatostatin, Somatostatin-14, octreotide, and a derivative thereof, as well as a pharmacologically 0159) As used herein, the term “leukotriene receptorago acceptable salt thereof. nist’ means a Substance having the function of acting on a Octreotide is represented by the formula: leukotriene receptor, and includes, for example, a BLT recep (0167 toragonist. 0160. As used herein, the term “BLT receptor agonist' means a Substance having the function of acting on a BLT receptor. Examples of the BLT receptor agonist include leu kotriene B4, CAY10583 and a derivative thereof, as well as a pharmacologically acceptable salt thereof. 0161 Leukotriene B4 is represented by the formula: US 2014/0220079 A1 Aug. 7, 2014 20

0168 As used herein, the term “cannabinoid receptorago (0174 VU0361737 is represented by the formula: nist’ means a Substance having the function of acting on a cannabinoid receptor. Examples of the cannabinoid receptor agonist include dronabinol, nabilone, levonantradol, otena 21 NN bant, GW833972A, GW405833, and a derivative thereof, as well as a pharmacologically acceptable salt thereof. Nu - O N 0169 Dronabinol is represented by the formula: O C

OH 0.175. As used herein, the term “phospholipase A2 inhibi H tor” means a Substance having the function of inhibiting the activity of phospholipase A2. Examples of the phospholipase H A2 inhibitor include glycyrrhizic acid, glycyrrhetic acid, and a derivative thereof, as well as a pharmacologically accept O able salt thereof. 0176 Glycyrrhetic acid is represented by the formula: 0170 As used herein, the term “sphingosine-1 phosphate receptor agonist’ means a Substance having the function of acting on a sphingosine-1 phosphate receptor. Examples of the sphingosine-1 phosphate receptoragonist include fingoli mod, ponesimod, RPC-1063, ONO-4641, SEW2871, sphin gosine-1 phosphate and a derivative thereof, as well as a pharmacologically acceptable salt thereof. 0171 Fingolimod is represented by the formula:

CH3

OH

OH. NH2 (0177. As used herein, the term “TGF-B production inhibi tor” means a Substance having the function of inhibiting production of TGF-B. Examples of the TGF-(3 production 0172. As used herein, the term “metabotropic glutamate inhibitor include pirfenidone, tranilast, and a derivative receptor agonist’ means a Substance having the function of thereof, as well as a pharmacologically acceptable salt acting on a metabotropic glutamate receptor, and includes, for thereof. example, an mGluR2 receptor agonist, an mGluR3 receptor agonist, an mGluR4 receptor agonist, an mGluR6 receptor 0.178 Firfenidone is represented by the formula: agonist, an mGluR7 receptor agonist, and an mGluR8 recep toragonist. 0173 As used herein, the term “mCluR2 receptoragonist' means a Substance having the function of acting on an mGluR2 receptor. The term “mCluR3 receptor agonist' means a Substance having the function of acting on an ( )-() mGluR3 receptor. The term “mCluR4 receptor agonist' means a Substance having the function of acting on an O mGluR4 receptor. The term “mCluR6 receptor agonist' means a Substance having the function of acting on an mGluR6 receptor. The term “mCluR7 receptor agonist' means a Substance having the function of acting on an mGluR7 receptor. The term “mCluR8 receptor agonist' (0179. As used herein, the term “Th2 cytokine inhibitor” means a Substance having the function of acting on an means a Substance having the function of inhibiting produc mGluR8 receptor. Examples of the mGluR2 receptoragonist, tion of a Th2 cytokine such as IL-4 and IL-5. Examples of the and/or the mGluR3 receptor agonist, and/or the mGluR4 Th2 cytokine inhibitor include Suplatast and a derivative receptoragonist, and/or the mGluR6 receptoragonist, and/or thereof, as well as a pharmacologically acceptable salt the mGluR7 receptor agonist, and/or the mGluR8 receptor thereof. Examples of the pharmacologically acceptable salt agonist include VU0361737, VU0155041, biphenylindanone of Suplatast include Suplatast tosylate. In a preferable aspect A, PBDA, L-AP4, and a derivative thereof, as well as a of the present invention, the Th2 cytokine inhibitor is pharmacologically acceptable salt thereof. Suplatast tosylate. US 2014/0220079 A1 Aug. 7, 2014 21

0180 Suplatast tosylate is represented by the formula: inhibitor, adenylate cyclase inhibitor, omega-3 fatty acid, PPAR agonist, dopamine receptor antagonist, dopamine receptoragonist, histamine receptoragonist, histamine recep CH3 tor antagonist, serotonin receptor agonist, serotonin receptor antagonist, Vasopressin receptor antagonist, Vasopressin receptor agonist, muscarine receptor antagonist, muscarine receptor agonist, adrenalin receptor antagonist, adrenalin O receptoragonist, angiotensin receptor agonist, GABA recep H3 ~~~ toragonist, thrombin receptor antagonist, thrombin receptor HO agonist, opioid receptor agonist, ADP receptor agonist, leu kotriene receptor antagonist, leukotriene receptor agonist, OESEO. melatonin receptor agonist, somatostatin receptor agonist, cannabinoid receptor agonist, sphingosine-1 phosphate receptor agonist, metabotropic glutamate receptor agonist, phospholipase A2 inhibitor, TGF-3 production inhibitor, and Th2 cytokine inhibitor. Examples of the immunomodulatory Small molecule drug include bestatin, pidotimod, levamisole, CH golotimod, forphenicinol, and a derivative thereof, as well as a pharmacologically acceptable salt thereof. Examples of the pharmacologically acceptable Salt of levamisole include 0181. As used herein, the “pharmacologically acceptable levamisole hydrochloride. acid as a second cellular immunity induction promoter that 0.184 Bestatin is represented by the formula: can be contained in the composition of the present invention means an acid which has no harmful effect on a subject to which the composition is administered, and does not impair HO O the pharmacological activity of the ingredients in the compo sition. In a preferable aspect of the present invention, the pharmacologically acceptable acid is an organic acid, more N preferably an organic compound containing carboxyl group H CU OH or an organic compound containing Sulfo group, more pref erably saturated or unsaturated Straight or branched fatty acid HC CH3. in which the saturated straight chain part has 8 to 20 carbon atoms, lactic acid, malic acid, salicylic acid, maleic acid, 0185. Pidotimod is represented by the formula: citric acid, or an organic compound containing Sulfo group, more preferably Saturated or unsaturated Straight or branched fatty acid in which the saturated straight chain part has 8 to 16 O carbon atoms, lactic acid, malic acid, salicylic acid, maleic O N-OH. acid, citric acid, an organic compound containing Sulfo group, further preferably fatty acid selected from the group I 1 N - consisting of decanoic acid, lauric acid, myristic acid, isos O N tearic acid, palmitic acid, Stearic acid and oleic acid, or lactic S acid, salicylic acid, citric acid or methanesulfonic acid. 0182. As used herein, a “pharmacologically acceptable 0186 Levamisole hydrochloride is represented by the for salt” which can be contained in the composition of the present mula: invention means a salt which has no harmful effect on an the Subject to be administered with the composition, and does not impair the pharmacological activity of the ingredients in the H N S composition. Examples of pharmacologically acceptable salts include inorganic acid salts (e.g. hydrochloric acid salt ^ oHC. and phosphoric acid salt), organic acid salts (e.g. acetic acid Srr)N salt, phthalic acid salt, and TFA salt), metal salts (alkali metal salts (e.g. sodium salt and potassium salt), alkaline earth 0187. In the present invention, the immunomodulatory metal salts (e.g. calcium salt and magnesium salt), aluminum Small molecule drug is usually a compound having a molecu salt etc.), and amine salts (triethylamine salt, benzylamine lar weight of less than 1000, preferably less than 500. In a salt, diethanolamine salt, t-butylamine salt, dicyclohexy preferable aspect of the present invention, the immunomodu lamine salt, arginine salt, dimethylammonium salt, ammo latory Small molecule drug is one or more compounds nium salt etc.), but are not limited to them. selected from the group consisting of bestatin, pidotimod and 0183. As used herein, the term “immunomodulatory small levamisole hydrochloride. molecule drug' means a Substance which activates or Sup 0188 As above described, the inventors have found that presses immune cells such as a T cell, a NK cell, a macroph among various cellular immunity induction promoters, a TLR age and the like, and which does not correspond to any of the ligand, a cyclic dinucleotide, a helper peptide, an immuno aforementioned TLR ligand, cyclic dinucleotide, helper pep modulatory Small molecule drug, a cyclooxygenase inhibitor, tide, cyclooxygenase inhibitor, prostaglandin receptor a prostaglandin receptor antagonist, a prostaglandin receptor antagonist, prostaglandin receptor agonist, TSLP production agonist, a TSLP production inhibitor, an adenylate cyclase US 2014/0220079 A1 Aug. 7, 2014 22 inhibitor, an omega-3 fatty acid, a PPAR agonist, a dopamine increased or decreased remarkably, for example, by 2 times or receptor antagonist, a dopamine receptoragonist, a histamine more such as by 4 times or more, as compared with the other receptoragonist, a histamine receptor antagonist, a serotonin cells in the same tissue. The term "overexpression” means receptor agonist, a serotonin receptor antagonist, a vaso that the abnormal expression is an increase in the expression pressin receptor antagonist, a vasopressin receptor agonist, a level. The expression level of a gene can be easily measured muscarine receptor antagonist, a muscarine receptor agonist, using any method well-known in the art. an adrenaline receptorantagonist, an adrenaline receptorago 0.192 As used herein, the term “subject” means any ani nist, an angiotensin receptor agonist, a GABA receptor ago mal having the HER2/neu gene, immune response of which nist, a thrombin receptor antagonist, a thrombin receptorago can be induced by the transdermal administration of a cancer nist, an opioid receptor agonist, an ADP receptor agonist, a vaccine composition fortransdermal administrationata prac leukotriene receptor antagonist, a leukotriene receptor ago tical stage. Typically, the Subject may be a mammal Such as nist, a melatonin receptor agonist, a Somatostatin receptor human, mouse, rat, dog, cat, rabbit, horse, cow, sheep, pig, agonist, a cannabinoid receptor agonist, a sphingosine-1 goat, monkey, and chimpanzee. A particularly preferable Sub phosphate receptor agonist, a metabotropic glutamate recep ject is human. toragonist, a phospholipase A2 inhibitor, a TGF-B production inhibitor, and a Th2 cytokine inhibitor are particularly suit II. CANCERVACCINE COMPOSITION FOR able for the mucosal administration of a HER2/neu E75 pep MUCOSALADMINISTRATION tide and/or a modified HER2/neu E75 peptide. Therefore, in an aspect of the present invention, the cellular immunity (0193 The usefulness of the HER2/neu E75 peptide as a induction promoter of the present invention is one or more cancer vaccine has been already apparent (Non-Patent Docu Substances selected from them. In further aspect, Such a Sub ment 3, Non-Patent Document 4). stance is a first cellular immunity induction promoter. In a 0194 As used herein, the term, composition for “mucosal particularly preferred aspect of the present invention, the administration” means any formulation or preparation which cellular immunity induction promoteris a combination of one is usually used for mucosal administration, for example, Sub or more Substances selected from a TLR ligand, a cyclic lingual, transnasal, buccal, rectal or vaginal administration. dinucleotide, an immunomodulatory Small molecule drug, a The composition may be, for example, a semisolid formula cyclooxygenase inhibitor, a prostaglandin receptor antago tion Such as a gel formulation (jelly formulation), a cream nist, a prostaglandin receptor agonist, a TSLP production formulation, an ointment, and a plaster formulation; a liquid inhibitor, an adenylate cyclase inhibitor, an omega-3 fatty formulation; a solid formulation Such as a powdered formu acid, a PPAR agonist, a dopamine receptor antagonist, a lation, a fine granule formulation, a granule formulation, a dopamine receptor agonist, a histamine receptor agonist, a film formulation, a tablet and an orally-disintegrating tablet: histamine receptor antagonist, a serotonin receptor agonist, a a mucosal spray formulation Such as an aerosol formulation; serotonin receptor antagonist, a vasopressin receptor antago and an inhalant formulation. Grouping, definition, a nature, a nist, a vasopressin receptor agonist, a muscarine receptor production process and the like of these formulations are well antagonist, a muscarine receptoragonist, an adrenaline recep known in the art. For example, see the Japanese Pharmaco tor antagonist, an adrenaline receptoragonist, an angiotensin poeia, 16" Edition. receptoragonist, a GABA receptoragonist, a thrombin recep 0.195 For example, as a solvent for liquid formulation, an torantagonist, a thrombin receptoragonist, an opioid receptor appropriate amount of water or solvent Such as ethanol, glyc agonist, an ADP receptor agonist, a leukotriene receptor erin or propylene glycol can be used, and a liquid formulation antagonist, a leukotriene receptoragonist, a melatonin recep can be prepared by dispersing or dissolving ingredients in the tor agonist, a Somatostatin receptor agonist, a cannabinoid solvent. receptoragonist, a sphingosine-1 phosphate receptoragonist, 0196. As the base for gel formulation (jelly formulation), a metabotropic glutamate receptor agonist, a phospholipase for example, a carboxyvinyl polymeras a hydrogelbase, agel base, a fat-free ointment, polyvinylpyrrolidone, polyvinyl A2 inhibitor, a TGF-B production inhibitor and a Th2 cytok alcohol, Sodium polyacrylate, carboxymethyl cellulose, ine inhibitor, and a helper peptide. The induction of cellular starch, Xanthan gum, karaya gum, sodium alginate, methyl immunity can be determined quantitatively by a variety of cellulose, hydroxypropyl cellulose, hydroxypropyl methyl known methods. Any of those known method, for example, cellulose phthalate (HPMCP), cellulose acetate phthalate the ELISPOT method described in Examples may be used in (CAP), carboxymethyl ethyl cellulose (CMEC), ethyl cellu this application. lose, hydroxyethyl cellulose, hydroxypropyl methyl cellu 0189 As used herein, non-invasive administration means lose, a carboxyvinyl polymer, tragacanth gum, gum arabic, administration without actively giving physical irritation and/ taragum, tamarind seed gum, psyllium seed gum, agar, gellan or chemical irritation, preferably without giving physical irri gum, glucomannan, locust bean gum, guar gum, carrageenan, tation (e.g. without giving irritation by mucosal peeling treat dextrin, dextran, amylose, carboxymethyl cellulose potas ment, mucosal damaging treatment, and mucosal perforation sium, carboxymethyl cellulose Sodium, carboxymethyl cel treatment) to a mucosa. lulose calcium, pullulan, chitosan, carboxymethyl starch 0190. As used herein, the term “cancer” means cancer Sodium, Plantago testa, galactomannan, eudragit, casein, alg associated with abnormal expression, for example, overex inic acid alkyl esters, gelatin, and polyethylene glycol can be pression of the HER2/neu gene. Examples of cancer may used. These bases can be dissolved in a solvent to prepare a include adenocarcinoma. Examples of the adenocarcinoma gel formulation having fluidity or a gel formulation having associated with abnormal expression of a HER2/neu gene formability. The solvent is preferably water, while glycerin or include, but are not limited to, breast cancer and prostate propylene glycol can also be used. CaCC. 0.197 Examples of the base for cream formulation include 0191 As used herein, the term “abnormal expression of a water/oil type bases Such as hydrophilic ointment and van gene' means that the expression level of the gene in a cell is ishing cream; and oil/water type bases Such as hydrophilic US 2014/0220079 A1 Aug. 7, 2014

petrolatum, purified lanolin, Aquahole, Eucerin, Neocerin, 0.1% to 30% by weight, relative to the total weight of the hydrated lanolin, cold cream, and hydrophilic plastibase. A composition. In an aspect, the composition of the present cream formulation can be prepared by adding these bases into invention contains the cellular immunity induction promoter oil and fat-based solvents or water, and stirring the mixture at preferably in an amount of 0.001% to 30% by weight, and high speed using a homogenizer or the like. more preferably 0.01% to 20% by weight, relative to the total 0198 Examples of the base for film formulation include weight of the composition. polyvinylpyrrolidone, polyvinyl alcohol, Sodium polyacry 0203 Further, the composition of the present invention late, carboxymethyl cellulose, starch, Xanthan gum, karaya may contain an additive, if necessary. The additive is selected gum, sodium alginate, methyl cellulose, a carboxyvinyl poly from, for example, isotonizing agents, antiseptics/germi mer, agar, hydroxypropyl cellulose, hydroxypropyl methyl cides, antioxidants, resolvents, solubilizers, Suspending cellulose phthalate (HPMCP), cellulose acetate phthalate agents, fillers, pH adjusting agents, stabilizers, absorption (CAP), carboxymethyl ethyl cellulose (CMEC), ethyl cellu promoters, release rate controlling agents, colorants, plasti lose, hydroxyethyl cellulose, hydroxypropyl methyl cellu cizers, adhesives and combinations of two or more of them, lose, a carboxyvinyl polymer, tragacanth gum, gum arabic, depending on the compatibility with the main ingredient of locust bean gum, guar gum, carrageenan, dextrin, dextran, the base, the HER2/neu E75 peptide and/or modified HER2/ amylose, carboxymethyl cellulose potassium, carboxym neu E75 peptide and the cellular immunity induction pro ethyl cellulose sodium, carboxymethyl cellulose calcium, moter, the intended administration regimen and the like. pullulan, chitosan, carboxymethyl starch sodium, Plantago (0204. The therapeutically effective amount of the HER2/ testa, galactomannan, aminoalkyl methacrylate copolymer E. neu E75 peptide and/or the modified HER2/neu E75 peptide aminoalkyl methacrylate copolymer RS, methacrylic acid may widely vary depending on severity of the disease, age copolymer L. methacrylic acid copolymer LD, methacrylic and relative health of the subject and other known factors. In acid copolymer S. methyl acrylate-methacrylic acid-methyl general, satisfactory result may be obtained at a one day dose methacrylate copolymer, ethyl acrylate-methyl methacrylate of about 0.1 ug to 1 g/kg body weight. The cellular immunity copolymer, polyvinyl acetal diethyl aminoacetate, casein, induction promoter is administered simultaneously with the and alginic acid alkyl ester. A film formulation can be pre HER2/neu E75 peptide and/or the modified HER2/neu E75 pared by dissolving these bases in water or an organic polar peptide or sequentially, and preferably, it is administered Solvent Such as ethanol, applying the solution into a thin film, simultaneously with the peptide. The effective amount of the and drying the solution. In one preferred aspect, the vaccine cellular immunity induction promoter may widely vary composition for mucosal administration of the present inven depending on the kind of cellular immunity induction pro tion is in the form of a film formulation. moter to be used, the presence or absence of other cellular 0199 For example, the powder formulation, the fine gran immunity induction promoter and the like, and satisfactory ule formulation, the granule formulation and the tablet can be result is obtained at a one day dose of about 0.01 ug to 1 g/kg prepared by mixing excipients such as lactose, corn starch body weight. The one day dose may be administered in a and crystalline cellulose; binders such as hydroxypropyl cel single dose or in several divided portions at several times Such lulose and gum arabic; and an appropriate amount of a solvent as two times or more, for example, two, three, four or five Such as water or ethanol, and then Subjecting the mixture to times. The administration interval may be arbitrary, but is granulation, drying, tableting or combination thereof. If nec appropriately selected from, for example, once per one day, essary, a lubricant such as magnesium Stearate, and a coating once per 3 days, once per one week, once per 2 weeks, once agent such as hydroxypropyl cellulose or Sucrose can also be per one month, once per 3 months, once per 6 months, once added. per one year, or an interval of administration longer than that, 0200 Examples of the base for an orally-disintegrating depending on the state of the patient, severity of cancer, tablet (freeze-dried type) include gelatin and polysaccharides whether it is for therapeutic purpose or preventive purpose, or Such as pullulan. Further, mannitol, trehalose, Sorbitol, gly the like. Generally, for the purpose of treating a patient actu cine and the like can also be used as a forming agent. An ally having a severe cancer, the HER2/neu E75 peptide and/or orally-disintegrating tablet (freeze-dried type) can be pre modified HER2/neu E75 peptide are administered at a higher pared by dissolving these additives in water, dispensing the frequency and a higher dose, while for the preventive purpose Solution, and freeze-drying the Solution. In one preferred for a patient having no cancer, the HER2/neu E75 peptide aspect, the vaccine composition for mucosal administration and/or modified HER2/neu E75 peptide are administered at a of the present invention is in the form of an orally-disintegrat lower frequency and a lower dose. ing tablet. 0205 The present invention will be explained in more 0201 For example, the aerosol formulation includes, as its detail and specifically below by way of Examples. The content, a liquid formulation, a gel formulation having high present invention is not limited to the Examples. fluidity, a cream formulation, and a fine powder Such as a powder formulation. These can be administered to a site of EXAMPLES administration Such as oral mucosa and nasal mucosa with 0206 Clofibrate: manufactured by LKT Laboratories, high efficiency, by dispersing solid or liquid microparticles in Inc., quercetin: manufactured by Cayman Chemical Co., res a gas using a spraying device. Veratrol (resveratrol (synthetic)): manufactured by Wako (0202) The amount of the HER2/neu E75 peptide and/or Pure Chemical Industries, Ltd., noscapine: manufactured by modified HER2/neu E75 peptide and the cellular immunity Wako Pure Chemical Industries, Ltd., 3,3'-diindolylmethane: induction promoter in the composition of the present inven manufactured by Wako Pure Chemical Industries, Ltd., Xan tion is not particularly limited. In an aspect, the composition thone: manufactured by Wako Pure Chemical Industries, of the present invention contains the HER2/neu E75 peptide Ltd., parthenolide: manufactured by Wako Pure Chemical and/or modified HER2/neu E75 peptide preferably in an Industries, Ltd., etodolac: manufactured by Wako Pure amount of 0.01% to 40% by weight, and more preferably Chemical Industries, Ltd., loxoprofen (loxoprofen Na): US 2014/0220079 A1 Aug. 7, 2014 24 manufactured by Yoshindo, Inc., diclofenac (diclofenac (0208 Both the HER2/neu E75 peptide and Peptide-25 sodium): manufactured by Wako Pure Chemical Industries, were chemically synthesized and purified by HPLC. Imiqui Ltd., ketoprofen: manufactured by Wako Pure Chemical mod was purchased from Tokyo Co., Ltd. Industries, Ltd., celecoxib: manufactured by Tocris Bio Cyclic di-GMP (c-di-GMP) and cyclic di-AMP (c-di-AMP) Science, docosahexaenoic acid: manufactured by Cayman were purchased from Biolog Life Science Institute GmbH. Chemical Co., 2',5'-dideoxyadenosine: manufactured by Bio Pam CSK manufactured by InvivoGen, Inc.; Zymosan mol International LP, SCH23390: manufactured by Wako manufactured by Nacalai Tesque, Inc.; Poly(I:C) manufac Pure Chemical Industries, Ltd., rotigotine: manufactured by tured by InvivoGen, Inc.; Pantoea bacterium-derived STARNASCENS, GW627368X: manufactured by Cayman lipopolysaccharide manufactured by Institute of Applied Chemical Co., Sulprostone: manufactured by Cayman Technology for Innate Immunity; glucopyranosyl lipid Chemical Co., cloprostenol: manufactured by Wako Pure manufactured by InvivoGen, Inc. (MPLAs); residuimod Chemical Industries, Ltd., BWA868C: manufactured by Cay (R848) and ODN1826 manufactured by InvivoGen, Inc.; man Chemical Co., RO1138452: manufactured by Cayman pidotimod manufactured by Santa Cruz, , Inc.; Chemical Co., leukotriene B4: manufactured by Cayman bestatine manufactured by Wako Pure Chemical Industries, Chemical Co., montelukast (montelukast sodium): LG Life Ltd.; levamisole hydrochloride manufactured by MP Bio Sciences, Ltd., zileuton: manufactured by Toronto Research medicals, LLC; peptidoglycan manufactured by InvivoGen, Chemicals, Inc., glycyrrhizic acid (dipotassium glycyr Inc.; Pam CSK manufactured by InvivoGen, Inc.; and rhizate): manufactured by Wako Pure Chemical Industries, flagellin manufactured by InvivoGen, Inc. were used. Ltd., pirfenidone: manufactured by Tocris Bioscience, diphenhydramine (diphenhydramine hydrochloride): manu Film Formulation factured by Wako Pure Chemical Industries, Ltd., famotidine: manufactured by Wako Pure Chemical Industries, Ltd., 0209. A film formulation was prepared according to the immepip (immepip dihydrobromide): manufactured by Toc formula described in the following Table 1. Specifically, 150 ris BioScience, proxyfan: manufactured by Tocris BioScience, parts by weight of purified water was added to 46 parts by 4-methylhistamine: manufactured by Tocris Bioscience, weight of D-mannitol (manufactured by Roquette) and 2.6 olanzapine: manufactured by Wako Pure Chemical Indus parts by weight of polyethylene glycol 400 (manufactured by tries, Ltd., Zolmitriptan: manufactured by Cipla, Ltd., tolvap Wako Pure Chemical Industries, Ltd.), and the mixture was tan: manufactured by Sigma-Aldrich Co., desmopressin: ultrasonically stirred. To the mixture, 46 parts by weight of manufactured by Sigma-Aldrich Co., oxybutynin (oxybuty hydroxypropyl cellulose (manufactured by Nippon Soda Co., nin hydrochloride): manufactured by Sigma-Aldrich, pilo Ltd., HPC-SSL), 5 parts by weight of HER2/neu E75 peptide carpine (pilocarpine hydrochloride): manufactured by Wako (TFA salt) (chemically synthesized and HPLC-purified prod Pure Chemical Industries, Ltd., tamsulosin (tamsulosin uct), 0.3 part by weight of Peptide-25 (chemically synthe hydrochloride): manufactured by Cipla, propranolol (propra sized and HPLC-purified product), and 0.1 part by weight of nolol hydrochloride): manufactured by Wako Pure Chemical a cellular immunity induction promoter other than the helper Industries, Ltd., xylazine: manufactured by Wako Pure peptide were added, and the mixture was mixed under suffi Chemical Industries, Ltd., novokinin: manufactured by cient stirring. The Solution in an amount equivalent to /100 of Sigma-Aldrich Co., baclofen: manufactured by Tokyo the original amount (2.5 parts by weight) was dropped on a Chemical Industry Co., Ltd., melatonin: manufactured by peelable film made of polyethylene terephthalate, and the LKT Laboratories, Inc., TRAP-6: manufactured by Bachem Solution was dried in air and dried under reduced pressure to Holding AG, adenosine diphosphate: manufactured by MP obtain 1 part by weight of film formulation. In the following Biomedicals, LLC, Somatostatin-14: manufactured by mouse immunity test, each film formulation was adminis Bachem Holding AG, GW405833; manufactured by Sigma tered in an amount of one sheet (10 mg)/time per one mouse. Aldrich Co., SEW2871: manufactured by Cayman Chemical The sources of the cellular immunity induction promoters Co., trimebutine (trimebutine maleate): manufactured by were the same as in the case of the liquid formulation for Tokyo Chemical Industry Co., Ltd., loperamide (loperamide Sublingual administration. hydrochloride): manufactured by Wako Pure Chemical Industries, Ltd., melatonin: manufactured by LKT Laborato Orally-Disintegrating Tablet ries, Inc., L-AP4 (L-2-amino-4-phsophonobutyric acid): 0210. An orally-disintegrating tablet was prepared manufactured by Wako Pure Chemical Industries, Ltd., and according to the formula described in the following Table 1. suplatast tosylate: manufactured by TOCRIS bioscience were Specifically, 48.6 parts by weight of D-mannitol (manufac used. tured by Roquette) and 46 parts by weight of fish-derived water-soluble gelatin were added to 400 parts by weight of Liquid Formulation for Sublingual Administration purified water, and then dissolved at 35°C. To the solution, 5 parts by weight of HER2/neu E75 peptide (TFA salt) (chemi 0207. A liquid formulation was prepared according to the cally synthesized and HPLC-purified product), 0.3 part by formula described in the following Table 1 and used as admin weight of Peptide-25 (chemically synthesized and HPLC istration samples for a mouse immunity test. Specifically, to a purified product), and 0.1 part by weight of a cellular immu HER2/neu E75 peptide (TFA salt), a cellular immunity induc nity induction promoter other than the helper peptide were tion promoter and optionally a pharmacologically acceptable added, and the mixture was mixed under Sufficient stirring. acid in the amounts described in Table 1, 20 parts by weight The Solution in an amount equivalent to /100 of the original of an additive (DMSO) and saline as a base were added to amount (5 parts by weight) was dropped on an aluminum foil, make up 100 parts by weight in total, and the mixture was and the solution was subjected to a freeze-drying treatment to mixed. Thus, a liquid formulation for Sublingual administra obtain 1 part by weight of an orally-disintegrating tablet. In tion was prepared. the mouse immunity test that will be described below, each US 2014/0220079 A1 Aug. 7, 2014

orally-disintegrating tablet was administered in an amount of antigen-specific cellular immunity induction was evaluated one tablet (10 mg)/time per mouse. The sources of purchase by the ELISPOT method described below. of the cellular immunity induction promoters were the same as in the case of the liquid formulation for Sublingual admin (ELISPOT Method) istration. 0212. A spleen cell suspension was prepared from the isolated spleen. Spleen cells (3x10° cells/well) and the anti Mouse Immunization Test 1 (Sublingual Administration) gen peptide (100 uM) together with culturing medium were placed into a well of an ELISPOT plate on which anti-mouse 0211. A mouse immunization test was carried out for the IFN-Y antibody was immobilized, and the cells were co liquid formulation for Sublingual administration, film formu cultured for 20 hours under the culture conditions of 37° C. lation and orally-disintegrating tablet. The test was carried and 5% CO. The number of INF-7 producing cell spots out according to an ELISPOT method. Specifically, in the (number of spots/3x10° cells) was evaluated. case of single administration, after the mouse was anesthe 0213. The results of the immunization test are shown in the tized, the liquid formulation, the film formulation or the following Table 1 together with the dose and the number of orally-disintegrating tablet was administered in the Sublin administrations. The mouse used was a genetically modified gual region and kept for 2 minutes, and then the mouse was mouse which can be used to evaluate the cellular immunity reared for 6 days. In the case of double administration, the inducing ability of a HLA-A*0201 type MHC restricted pep above-described operation was repeated in the same manner tide. Furthermore, for a comparison, the result of the follow 6 days after the first administration. The spleen was isolated 6 ing immunization using an injectable formulation (Compara days after the day of final administration, and the level of tive Example 2) is described in the last part of Table 1. TABLE 1

Results of immunization (ELISPOT Composition average Antigen Cellular immunity Admini- number Dosage form Base peptide induction promoter Acid Dose stration of spots) Comparative liqui Saline HER2/neu None None None 20 LL 2 times 3 example 1 ormulation E75(1.25) Example 1 iqui Saline HER2/neu LPS(TLR4 ligand) None None 20 LL 2 times 15 ormulation E75(1.25) (0.1) Example 2 iqui Saline HER2/neu None PEP(0.3) None 20 LL 2 times 11 ormulation E75(1.25) Example 3 iqui Saline HER2/neu LPS(TLR4 ligand) PEP(0.3) None 20 LL 2 times 30 ormulation E75(1.25) (0.1) Example 4 iqui Saline HER2/neu LPS(TLR4 ligand) PEP(0.3) MA(0.05) 20 LL 2 times 41 ormulation E75(1.25) (0.1) Example 5 iqui Saline HER2/neu LPS(TLR4 ligand) PEP (0.3) isostearic 20 LL 2 times 38 ormulation E75(1.25) (0.1) acid (0.05) Example 6 iqui Saline HER2/neu LPS(TLR4 ligand) PEP(0.3) lactic acid 20 L 2 times 37 ormulation E75(1.25) (0.1) (0.05) Example 7 iqui Saline HER2/neu LPS(TLR4 ligand) PEP (0.3) citric acid 20 LL 2 times 38 ormulation E75(1.25) (0.1) (0.05) Example 8 iqui Saline HER2/neu syn-MPL(TLR4 PEP(0.3) None 20 LL 2 times 27 ormulation E75 (1.25) ligand) (0.1) Example 9 iqui Saline HER2/neu imiquimod (TLR7 PEP(0.3) None 20 LL 2 times 89 ormulation E75 (1.25) and/or TLR8 igand) (0.3) Example 10 liqui Saline HER2/neu residuimod (TLR7 PEP(0.3) None 20 LL 2 times 177 ormulation E75 (1.25) and/or TLR8 igand) (0.1) Example 11 liqui Saline HER2/neu c-di-GMP(cyclic None None 10 LIL 1 time 523 ormulation E75 (1.25) dinucleotide) (0.2) Example 12 liqui Saline HER2/neu c-di-GMP(cyclic PEP(0.3) None 10 LIL 1 time 611 ormulation E75 (1.25) dinucleotide) (0.2) Example 13 liqui Saline HER2/neu levamisole HCI None None 20 LL 2 times 45 ormulation E75 (1.25) (immunomodulatory Small molecule drug) (0.5) Example 14 liquid Saline HER2/neu levamisole PEP(0.3) None 20 L 2 times 70 ormulation E75 (1.25) HCl (immunomodulatory Small molecule drug) (0.5) US 2014/0220079 A1 Aug. 7, 2014 26

TABLE 1-continued

Results of immunization (ELISPOT Composition average Antigen Cellular immunity Admini- number Dosage form Base peptide induction promoter Acid Dose stration of spots) Example 15 Saline HER2/neu. Bestatin (immunomodulatory PEP(0.3) None 20LL 2 times ormulation E75 (1.25) Small molecule drug) (0.5) Example 16 Saline HER2/neu. pidotimod(immunomodulatory PEP(0.3) None 20LL 2 times ormulation E75 (1.25) Small molecule drug) (0.5) Example 17 Saline HER2/neu. clofibrate(PPAR PEP(0.3) None 20LL 2 times 85 ormulation E7 5 (1.25) agonist) (0.1) Example 18 Saline ER2/neu. quercetin(TSLP None None 20LL 2 times 67 ormulation 7 5 (1.25) production inhibitor) (0.1) Example 19 Saline ER2/neu. quercetin(TSLP PEP(0.3) None 20LL 2 times 94 ormulation 7 5 (1.25) production inhibitor) (0.1) Example 20 Saline ER2/neu. noscapine(TSLP PEP(0.3) None 20LL 2 times 78 ormulation 7 5 (1.25) production inhibitor) (0.1) Example 21 Saline ER2/neu. 3,3'-diindolylmethane PEP(0.3) None 20LL 2 times ormulation 7 5 (1.25) (TSLP production inhibitor) (0.1) Example 22 Saline ER2/neu. Xanthone(TSLP PEP(0.3) None 20LL 2 times 110 ormulation 7 5 (1.25) production inhibitor) (0.1) Example 23 Saline HER2/neu. parthenolide(TSLP PEP(0.3) None 20LL 2 times 105 ormulation E7 5 (1.25) production inhibitor) (0.1) Example 24 Saline ER2/neu. Oxoprofen(COX None None 20LL 2 times 56 ormulation 7 5 (1.25) inhibitor) (0.1) Example 25 Saline ER2/neu. Oxoprofen(COX C E P(0.3) None 20LL 2 times 89 ormulation 7 5 (1.25) inhibitor) (0.1) Example 26 Saline ER2/neu. etodolac(COX C E P(0.3) None 20LL 2 times 78 ormula ion 75 (1.25) inhibitor) (0.1) Example 27 Saline ER2/neu. diclofenac(COX C E P(0.3) None 20LL 2 times ormulation 75 (1.25) inhibitor) (0.1) Example 28 Saline ER2/neu. ketoprofen (CCX C E P(0.3) None 20LL 2 times ormula ion 7 5 (1.25) inhibitor) (0.1) Example 29 Saline ER2/neu. celecoxib (COX C E P(0.3) None 20LL 2 times 123 ormulation 75 (1.25) inhibitor) (0.1) Example 30 Saline ER2/neu. docosahexaenoic C E P(0.3) None 20LL 2 times ormulation 75 (1.25) acid (omega-3 fatty acid) (0.1) Example 31 iqui Saline ER2/neu. 2',5'-dideoxyadenosine C E P(0.3) None 20LL 2 times ormulation 75 (1.25) (adenylate cyclase inhibitor) (0.1) Example 32 iquid Saline HER2/neu. SCH23390 PEP(0.3) None 20 IL 2 times ormulation E75 (1.25) (dopamine receptor antagonist) (0.1) Example 33 iquid Saline HER2/neu. rotigotine(dopamine PEP(0.3) None 20 IL 2 times ormulation E75 (1.25) receptor agonist) (0.1) Example 34 iquid Saline HER2/neu. GW627368X(prostaglandin PEP(0.3) None 20 IL 2 times 85 ormulation E75 (1.25) receptor antagonist) (0.1) Example 35 iquid Saline HER2/neu. Sulprostone(prostaglandin PEP(0.3) None 20 IL 2 times 89 ormulation E75 (1.25) receptor agonist) (0.1) US 2014/0220079 A1 Aug. 7, 2014 27

TABLE 1-continued

Results of immunization (ELISPOT Composition average Antigen Cellular immunity Admini- number Dosage form Base peptide induction promoter Acid Dose stration of spots) Example 36 liquid Saline HER2/neu BWA868C PEP(0.3) None 20 IL 2 times 76 ormulation E75 (1.25) (prostaglandin receptor antagonist) (0.1) Example 37 liquid Saline HER2/neu RO11384.52 PEP(0.3) None 20 IL 2 times 87 ormulation E75 (1.25) (prostaglandin receptor antagonist) (0.1) Example 38 liquid Saline HER2/neu montelukast(leukotriene PEP(0.3) None 20 IL 2 times ormulation E75 (1.25) receptor antagonist) (0.1) Example 39 liquid Saline HER2/neu Zileuton(leukotriene PEP(0.3) None 20 IL 2 times ormulation E75 (1.25) receptor antagonist) (0.1) Example 40 liquid Saline HER2/neu dipotassium PEP(0.3) None 20 IL 2 times ormulation E75 (1.25) glycyrrhizinate (phospholipase A2 inhibitor) (0.1) Example 41 liquid Saline HER2/neu pirfenidone(TGF- PEP(0.3) None 20 IL 2 times ormulation E75 (1.25) beta production inhibitor) (0.1) Example 42 liquid Saline HER2/neu diphenhydramine PEP(0.3) None 20 IL 2 times 76 ormulation E75 (1.25) (histamine receO antagonist) (0.1) Example 43 liquid Saline HER2/neu famotidine(histamine PEP(0.3) None 20 IL 2 times 86 ormulation E75 (1.25) receptor antagonist) (0.1) Example 44 liquid Saline HER2/neu proxyfan(histamine PEP(0.3) None 20 IL 2 times 65 ormulation E75 (1.25) receptor agonist) (0.1) Example 45 liquid Saline HER2/neu 4-methylhistamine PEP(0.3) None 20 IL 2 times ormulation E75 (1.25) (histamine receO agonist) (0.1) Example 46 liqui Saline HER2/neu olanzapine?serotonin PEP(0.3) None 20LL 2 times 55 ormulation E75 (1.25) receptor antagonist) (0.1) Example 47 liqui Saline HER2/neu Zolmitriptan(serotonin PEP(0.3) None 20LL 2 times 95 ormulation E75 (1.25) receptor agonist) (0.1) Example 48 liqui Saline HER2/neu tolvaptan(vasopressin PEP(0.3) None 20LL 2 times ormulation E75 (1.25) receptor antagonist) (0.1) Example 49 liqui Saline HER2/neu desmopressin(vasopressin PEP(0.3) None 20LL 2 times ormulation E75 (1.25) receptor agonist) (0.1) Example 50 liqui Saline HER2/neu oxybutynin (muscarine PEP(0.3) None 20LL 2 times 56 ormulation E75 (1.25) receptor antagonist) (0.1) Example 51 liqui Saline HER2/neu pilocarpine(muscarine PEP(0.3) None 20LL 2 times ormulation E75 (1.25) receptor agonist) (0.1) Example 52 liqui Saline HER2/neu tamsulosin(adrenalin PEP(0.3) None 20LL 2 times 67 ormulation E75 (1.25) receptor antagonist) (0.1) US 2014/0220079 A1 Aug. 7, 2014 28

TABLE 1-continued

Results of immunization (ELISPOT Composition average Antigen Cellular immunity Admini- number Dosage form Base peptide induction promoter Acid Dose stration of spots) Example 53 liqui Saline HER2/neu propranolol (adrenalin PEP(0.3) None 20LL 2 times 67 ormulation E75 (1.25) receptor antagonist) (0.1) Example 54 liqui Saline HER2/neu xylazine(adrenalin PEP(0.3) None 20LL 2 times ormulation E75 (1.25) receptor agonist) (0.1) Example 55 liqui Saline HER2/neu novokinin(angiotensin PEP(0.3) None 20LL 2 times ormulation E75 (1.25) receptor agonist) (0.1) Example 56 liqui Saline HER2/neu baclofen (GABA PEP(0.3) None 20LL 2 times ormulation E75 (1.25) receptor agonist) (0.1) Example 57 liqui Saline HER2/neu melatonin (melatonin PEP(0.3) None 20LL 2 times 76 ormulation E75 (1.25) receptor agonist) (0.1) Example 58 liqui Saline HER2/neu adenosine PEP(0.3) None 20LL 2 times ormulation E75 (1.25) diphosphate(ADP receO agonist) (0.1) Example 59 liqui Saline HER2/neu trimebutine(muscarine PEP(0.3) None 20LL 2 times ormulation E75 (1.25) receptor antagonist) (0.1) Example 60 liqui Saline HER2/neu L-AP4(metabotropic PEP(0.3) None 20LL 2 times 67 ormulation E75 (1.25) glutamate receptor agonist) (0.1) Example 61 liqui Saline HER2/neu TRAP-6(thrombin PEP(0.3) None 20LL 2 times ormulation E75 (1.25) receptor agonist) (0.1) Example 62 liqui Saline HER2/neu loperamide PEP(0.3) None 20LL 2 times 76 ormulation E75 (1.25) (opioid receptor agonist) (0.1) Example 63 liqui Saline HER2/neu leukotriene PEP(0.3) None 20LL 2 times ormulation E75 (1.25) B4(leukotriene receptor agonist) (0.1) Example 64 liquid Saline HER2/neu Somatostatin-14 PEP(0.3) None 20 IL 2 times ormulation E75 (1.25) (somatostatin receptor agonist) (0.1) Example 65 liquid Saline HER2 file GW40583.3 PEP(0.3) None 20 IL 2 times ormulation E75 (1.25) (cannabinoid receptor agonist) (0.1) Example 66 liquid Saline HER2/neu SEW2871 (sphingosine- PEP(0.3) None 20 IL 2 times ormulation E75 (1.25) 1 phosphate receptor agonist) (0.1) Example 67 liquid Saline HER2/neu Suplatast PEP(0.3) None 20 IL 2 times ormulation E75 (1.25) tosylate (Th2 cytokine inhibitor) (0.1) Example 68 liquid Saline HER2/neu LPS(TLR4 ligand) PADRE None 20 IL 2 times 33 ormulation E75 (1.25) (0.1) (0.3) Example 69 film HPC/PEG, HER2/neu LPS(TLR4 ligand) PEP(0.3) None 10 mg 2 times 32 ormulation mannitol E75(5) (0.1) Example 70 film HPC/PEG, HER2/neu c-di-GMP (cyclic PEP(0.3) None 10 mg 2 times 651 ormulation mannitol E75(5) dinucleotide) (0.1) Example 71 film HPC/PEG, HER2/neu quercetin(TSLP PEP(0.3) None 10 mg 2 times 104 ormulation mannitol E75(5) production inhibitor) (0.1) US 2014/0220079 A1 Aug. 7, 2014

TABLE 1-continued

Results of immunization (ELISPOT Composition average Antigen Cellular immunity Admini- number Dosage form Base peptide induction promoter Acid Dose stration of spots) Example 72 film HPC/PEG, HER2/neu loxoprofen(COX PEP(0.3) None 10 mg 2 times 95 formulation mannitol E75(5) inhibitor) (0.1) Example 73 orally-disintegrating gelatin HER2/neu LPS(TLR4 ligand) PEP(0.3) None 10 mg 2 times 33 tablet mannitol E75(5) (0.1) Example 74 orally-disintegrating gelatin HER2/neu c-di-GMP (cyclic PEP(0.3) None 10 mg 2 times 636 tablet mannitol E75(5) dinucleotide) (0.1) Example 75 orally-disintegrating gelatin HER2/neu quercetin(TSLP PEP(0.3) None 10 mg 2 times 101 tablet mannitol 575(5) production inhibitor) (0.1) Example 76 orally-disintegrating gelatin HER2/neu loxoprofen(COX PEP(0.3) None 10 mg 2 times 97 tablet mannitol E75(5) inhibitor) (0.1) Comparative Subcutaneous Saline HER2/neu Montanide ISA51VG None 200 IL 1 time 110 example 2 injection E75 (50) (0.125) Walues in the parentheses indicate the mixing proportions (parts by weight) of the respective components (The same also applies to the following tables), HPC: Hydroxypropyl cellulose PEG: Polyethylene glycol 400 LPS: Pantoea bacterium-derived polysaccharide syn-MPL: Synthetic monophospholipidA (glucopyranosyl lipid) c-di-GMP: Cyclic di-GMP Levamisole HCl: Levamisole hydrochloride PEP: Peptide-25 (SEQID NO:3) (helper peptide) PADRE:PADRE (SEQID NO:4) (helper peptide) MA: Myristic acid

Liquid Formulation for Nasal Administration mouse was anesthetized, the liquid formulation was admin 0214. A liquid formulation was prepared according to the istered by inhalation through the nasal cavity, and the mouse formula described in the following Table 2 and used as admin was reared for 6 days. In the case of double administration, istration sample for a mouse immunization test. Specifically, the operation described above was repeated in the same man to a HER2/neu E75 peptide and a cellular immunity induction ner 6 days after the first administration. The spleen was iso promoter in the amounts described in Table 2, 20 parts by lated 6 days after the day of final administration, and the level weight of additive (DMSO) and saline as a base were added to of antigen-specific cellular immunity induction was evalu make up 100 parts by weight in total, and then mixed. Thus, ated by an ELISPOT method. The ELISPOT method was a liquid formulation for nasal administration was prepared. carried out by the same method as that used in the mouse The sources of the HER2/neu E75 peptide and the cellular immunity test 1. immunity induction promoters were the same as in the case of 0216. The results of the immunization test are shown in the the liquid formulation for Sublingual administration. following Table 2 together with the dose and the number of administrations. The mouse used was a genetically modified Mouse Immunization Test 2 (Nasal Administration) mouse which can be used to evaluate the cellular immunity 0215. A mouse immunization test was carried out for the inducing ability of a HLA-A*0201 type MHC restricted pep liquid formulation for nasal administration described above. tide. Furthermore, for a comparison, the result of the follow The test was carried out according to an ELISPOT method. ing immunization using an injectable formulation (Compara Specifically, in the case of single administration, after the tive Example 2) is described in the last part of Table 2. TABLE 2

Results of immunization (ELISPOT Composition average Antigen Cellular immunity Admini- number Dosage form Base peptide induction promoter Dose stration of spots) Comparative liquid saline HER2/neu None None 10 L 2 times 3 example 3 formulation E75 (1.25) Example 77 liquid saline HER2/neu None PEP(0.3) 10 L 2 times 11 formulation E75 (1.25) US 2014/0220079 A1 Aug. 7, 2014 30

TABLE 2-continued

Results of immunization (ELISPOT Composition average Cellular immunity Admini number Dosage form induction promoter stration of spots) Exam ble 78 LPS (TLR4 None 2 times 16 ormulation ligand) (0.1) Exam ble 79 saline LPS (TLR4 PEP(0.3) 2 times 31 ormulation 7 5 ( 2 5 ) ligand) (0.1) Exam ble 8O saline Pam3CSK4 PEP(0.3) 2 times 69 ormulation (TLR1/2 ligand) (0.1) Exam ble 81 saline poly(I:C)(TLR3 PEP(0.3) 2 times 183 ormulation 7 5 ( .2 5 ) ligand) (0.1) Exam ble 82 saline c-di-GMP(cyclic PEP(0.3) 476 ormulation 7 5 ( .2 5 ) dinucleotide) (0.2) Exam ble 83 saline clofibrate(PPAR PEP(0.3) 2 times 87 ormula ion agonist) (0.1) Exam ble 84 saline quercetin(TSLP None 2 times ormulation production inhibitor) (0.1) Exam ble 85 saline quercetin(TSLP PEP(0.3) 2 times ormulation 7 5 ( .2 5 ) production inhibitor) (0.1) Exam ble 86 iqui saline resveratrol PEP(0.3) 2 times 132 ormulation (TSLP production inhibitor) (0.1) Example 87 iquid saline HER2/neu. loxoprofen (COX None 10 IL 2 times 89 ormulation E75 (1.25) inhibitor) (0.1) Example 88 iquid saline HER2/neu. loxoprofen (COX PEP(0.3) 10 IL 2 times 125 ormulation E75 (1.25) inhibitor) (0.1) Example 89 iquid saline HER2/neu. 2',5'-dideoxyadenosine PEP(0.3) 10 IL 2 times ormulation E75 (1.25) (adenylate cyclase inhibitor) (0.1) Example 90 iquid saline HER2/neu. SCH23390 PEP(0.3) 10 IL 2 times ormulation E75 (1.25) (dopamine receptor antagonist) (0.1) Example 91 iquid saline HER2/neu. rotigotine PEP(0.3) 10 IL 2 times ormulation E75 (1.25) (dopamine receptor agonist) (0.1) Exam ble 92 iquid saline HER2/neu. GW627368X PEP(0.3) 10 L.L 2 times 93 ormulation E75 (1.25) (prostaglandin receptor antagonist) (0.1) Exam ble 93 iquid saline HER2/neu. Sulprostone(prostaglandin PEP(0.3) 10 L.L 2 times 114 ormulation E75 (1.25) receptor agonist) (0.1) Exam ble 94 iquid saline HER2/neu. cloprostenol (prostaglandin PEP(0.3) 10 L.L 2 times ormulation E75 (1.25) receptor agonist) (0.1) Exam ble 95 iquid saline HER2/neu. montelukast(leukotriene PEP(0.3) 10 L.L 2 times ormulation E75 (1.25) receptor antagonist) (0.1) Exam ble 96 iquid saline HER2/neu. dipotassium PEP(0.3) 10 L.L 2 times ormulation E75 (1.25) glycyrrhizinate (phospholipase US 2014/0220079 A1 Aug. 7, 2014 31

TABLE 2-continued

Results of immunization (ELISPOT Composition average

Antigen Cellular immunity Admini number Dosage form Base peptide induction promoter Dose stration of spots)

A2 inhibitor)(0.1) Example 97 iquid saline HER2/neu. pirfenidone(TGF PEP(0.3) 10 IL 2 times ormulation E75 (1.25) beta production inhibitor) (0.1) Example 98 iquid saline HER2/neu. diphenhydramine PEP(0.3) 10 IL 2 times ormulation E75 (1.25) (histamine receO antagonist) (0.1) Exam e 99 ine HER2/neu. famotidine(histamine C E P(0.3) OLL 2 times 84 ormulation .25) receO antagonist) (0.1) Exam ine HER2/neu. proxyfan (histamine C E P(0.3) OLL 2 times ormulation .25) receO agonist) (0.1) Exam ine HER2/neu. olanzapine(serotonin C E P(0.3) OLL 2 times ormulation .25) (CeC) antagonist) (0.1) Exam ine HER2/neu. Zolmitriptan(serotonin C E P(0.3) OLL 2 times 65 ormulation .25) receO agonist) (0.1) Exam ine HER2/neu. tolvaptain (vasopressin C E P(0.3) OLL 2 times ormulation .25) receO antagonist) (0.1) Exam ine HER2/neu. desmopressin(vasopressin C E P(0.3) OLL 2 times ormulation .25) receO agonist) (0.1) Exam ine HER2/neu. pilocarpine(muscarine C E P(0.3) OLL 2 times ormulation .25) receO agonist) (0.1) Exam ine HER2/neu. tamsulosin(adrenalin C E P(0.3) OLL 2 times ormulation .25) receO antagonist) (0.1) Exam ine HER2/neu. propranolol (adrenalin C E P(0.3) OLL 2 times ormulation .25) receO antagonist) (0.1) Exam ine HER2/neu. xylazine(adrenalin C E P(0.3) OLL 2 times ormulation .25) receO agonist) (0.1) Exam ine HER2/neu. melatonin (melatonin C E P(0.3) OLL 2 times 76 ormulation .25) receO agonist) (0.1) Exam iqui ine HER2/neu. novokinin(angiotensin C E P(0.3) OLL 2 times ormulation .25) receptor agonist) (0.1) US 2014/0220079 A1 Aug. 7, 2014 32

TABLE 2-continued

Results of immunization (ELISPOT Composition average Antigen Cellular immunity Admini- number Dosage form Base peptide induction promoter Dose stration of spots) Example 111 liqui saline HER2/neu. baclofen (GABA PEP(0.3) OLL 2 times ormulation E75 (1.25) receptor agonist) (0.1) Example 112 liqui saline HER2/neu trimebutine(muscarine PEP(0.3) OLL 2 times ormulation E75 (1.25) receptor antagonist) (0.1) Example 113 liqui saline HER2/neu. L-AP4(metabotropic PEP(0.3) OLL 2 times 56 ormulation E75 (1.25) glutamate receO agonist) (0.1) Example 114 liqui saline HER2/neu. TRAP-6 PEP(0.3) OLL 2 times ormulation E75 (1.25) (thrombin receO agonist) (0.1) Example 115 liqui saline HER2/neu. loperamide(opioid PEP(0.3) OLL 2 times 67 ormulation E75 (1.25) receO agonist) (0.1) Example 116 liqui saline HER2/neu. leukotriene PEP(0.3) OLL 2 times ormulation E75 (1.25) B4(leukotriene receptor agonist) (0.1) Example 117 liqui saline HER2/neu. somatostatin-14 PEP(0.3) OLL 2 times ormulation E75 (1.25) (somatostatin receptor agonist) (0.1) Example 118 liqui saline HER2/neu. GW405833 PEP(0.3) OLL 2 times ormulation E75 (1.25) (cannabinoid receptor agonist) (0.1) Example 119 liqui saline HER2/neu. SEW2871 (sphingosine-1 PEP(0.3) 10 LIL 2 times ormulation E75 (1.25) phosphate receptor agonist) (0.1) Example 120 liqui saline HER2/neu. Suplatast PEP(0.3) 10 LIL 2 times ormulation E75 (1.25) tosylate(Th2 cytokine inhibitor) (0.1) Example 121 liquid saline HER2/neu. adenosine PEP(0.3) 10 LIL 2 times ormulation E75 (1.25) diphosphate(ADP receptor agonist) (0.1) Example 122 liquid saline HER2/neu. LPS (TLR4 PADRE 10 LIL 2 times 34 ormulation E75 (1.25) ligand) (0.1) (0.3) Comparative subcutaneous saline HER2/neu. Montanide ISA51VG 200LL 1 time 110 example 2 iniection E75 (0.125) (50) Poly(I:C): Polyinosinic-polycytidylic acid

Subcutaneous Injectable Formulation Mouse Immunization Test 3 (Subcutaneous Injection) 0217. A subcutaneous injectable formulation was pre 0218. A mouse immunization test was carried out for the pared according to the formula described in the following subcutaneous injectable formulation described above. The Table 3 and used as the administration sample for an immu test was carried out according to an ELISPOT method. Spe nization test. Specifically, to the HER2/neu 575 peptide and cifically, 200 uL of the injectable formulation was adminis Montanide ISA51VG (Freund Corporation) as an adjuvant in tered by Subcutaneous injection to the dorsal side of a mouse, the amounts described in Table 3, 0.5 part by weight of and then the mouse was reared for 6 days. The spleen was additive (DMSO) and saline as a base were added to make up isolated 6 days after the day of administration, and the level of 100 parts by weight in total, and then mixed to prepare an antigen-specific cellular immunity induction was evaluated injectable formulation. The source of the HER2/neu E75 by an ELISPOT method. The number of administration was peptide was the same as in the case of the liquid formulation set to once. The mouse used was a genetically modified for Sublingual administration. mouse which can be used to evaluate the cellular immunity US 2014/0220079 A1 Aug. 7, 2014 inducing ability of a HLA-A*0201 type MHC-restricted pep tide can be evaluated. The ELISPOT method was carried out by the same method as that used in the mouse immunization test 1. The results of the immunization test are shown in the following Table 3. TABLE 3 Composition Result of immunization Cellular immunity (ELISPOT average Base Antigen peptide induction promoter number of spots) Comparative saline HER2/neu E75 (0.125) Montanide ISA51VG(50) 110 Example 2

0219. A cancer vaccine composition for mucosal admin 0222 Regarding Sublingual administration, more prefer istration comprising HER2/neu E75 peptide and/or a modi ably, a first cellular immunity induction promoter selected fied HER2/neu E75 peptide and a first cellular immunity from TLR4 ligand, TLR7 and/or TLR8 ligand, cyclic dinucle induction promoter was administered in Sublingual (Table 1) otide, immunomodulatory Small molecule drug, cyclooxyge or nasal (Table 2) route, and an efficacy of the first cellular nase inhibitor, TSLP production inhibitor, prostaglandin immunity induction promoter was evaluated. receptor antagonist, prostaglandin receptor agonist, PPAR 0220. As a result, a cellular immunity induction promoter agonist, TGF-beta production inhibitor, histamine receptor selected from TLR ligand, cyclic dinucleotide, helper pep agonist, histamine receptor antagonist, serotonin receptor tide, immunomodulatory Small molecule drug, cyclooxyge agonist, serotonin receptor antagonist, muscarine receptor nase inhibitor, prostaglandin receptor antagonist, prostaglan antagonist, adrenalin receptor antagonist, opioid receptor din receptor agonist, TSLP production inhibitor, adenylate agonist, melatonin receptor agonist, metabotropic glutamate cyclase inhibitor, omega-3 fatty acid, PPAR agonist, dopam receptor agonist and a combination of two or more kinds of ine receptorantagonist, dopamine receptoragonist, histamine them, as well as a combination of a helper peptide with the receptor agonist, histamine receptor antagonist, serotonin first cellular immunity induction promoter other than helper receptor agonist, serotonin receptor antagonist, Vasopressin peptide were effective. receptor antagonist, vasopressin receptor agonist, muscarine 0223 Regarding nasal administration, further preferably, receptor antagonist, muscarine receptor agonist, adrenalin a first cellular immunity induction promoter selected from receptor antagonist, adrenalin receptor agonist, angiotensin TLR4 ligand, TLR1/2 ligand, TLR3 ligand, cyclic dinucle receptor agonist, GABA receptor agonist, thrombin receptor otide, immunomodulatory Small molecule drug, cyclooxyge agonist, opioid receptor agonist, ADP receptor agonist, leu nase inhibitor, TSLP production inhibitor, prostaglandin kotriene receptor antagonist, leukotriene receptor agonist, receptor antagonist, prostaglandin receptor agonist, PPAR melatonin receptor agonist, somatostatin receptor agonist, agonist, TGF-beta production inhibitor, histamine receptor cannabinoid receptor agonist, sphingosine-1 phosphate agonist, histamine receptor antagonist, serotonin receptor receptor agonist, metabotropic glutamate receptor agonist, agonist, serotonin receptor antagonist, muscarine receptor phospholipase A2 inhibitor, TGF-beta production inhibitor, antagonist, adrenalin receptor antagonist, opioid receptor Th2 cytokine inhibitor and a combination of two or more agonist, melatonin receptor agonist, metabotropic glutamate kinds of them, was preferable. 0221 Preferably, a first cellular immunity induction pro receptor agonist and a combination of two or more kinds of moter selected from TLR ligand, cyclic dinucleotide, immu them, as well as a combination of a helper peptide with the nomodulatory Small molecule drug, cyclooxygenase inhibi first cellular immunity induction promoter other than helper tor, TSLP production inhibitor, prostaglandin receptor peptide were effective. antagonist, prostaglandin receptor agonist, PPAR agonist, 0224. It was also confirmed that the induction of cellular TGF-beta production inhibitor, histamine receptor agonist, immunity is promoted by the addition of a pharmacologically histamine receptor antagonist, serotonin receptor agonist, acceptable acid or a pharmacologically acceptable salt serotonin receptor antagonist, muscarine receptor antagonist, thereofas a second cellular immunity induction promoter. adrenalin receptor antagonist, opioid receptor agonist, mela 0225. From the viewpoint of safety, a sublingual adminis tonin receptoragonist, metabotropic glutamate receptorago tration is preferable rather than a nasal administration. How nist and a combination of two or more kinds of them, as well ever, the strong induction of immunity was also confirmed as a combination of a helper peptide with the first cellular when a film formulation or an orally-disintegrating tablet, immunity induction promoter other than helper peptide were which is a preferable form in view of convenient administra effective. tion and storage stability, was used.

SEQUENCE LISTING

<16 Os NUMBER OF SEO ID NOS: 6

<21 Os SEQ ID NO 1 &211s LENGTH: 9 US 2014/0220079 A1 Aug. 7, 2014 34

- Continued

212. TYPE: PRT <213> ORGANISM: Homo sapiens

<4 OOs, SEQUENCE: 1 Lys Ile Phe Gly Ser Lieu Ala Phe Lieu. 1. 5

<210s, SEQ ID NO 2 &211s LENGTH: 2O &212s. TYPE: DNA <213s ORGANISM: Unknown 22 Os. FEATURE: <223> OTHER INFORMATION: Description of Unknown: Bacterial DNA sequence

<4 OOs, SEQUENCE: 2 tccatgacgt toctdacgtt 2O

<210s, SEQ ID NO 3 &211s LENGTH: 15 212. TYPE: PRT <213> ORGANISM: Mycobacterium tuberculosis

<4 OOs, SEQUENCE: 3 Phe Glin Asp Ala Tyr Asn Ala Ala Gly Gly His Asn Ala Val Phe 1. 5 1O 15

<210s, SEQ ID NO 4 &211s LENGTH: 13 212. TYPE: PRT <213> ORGANISM: Artificial Sequence 22 Os. FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic

22 Os. FEATURE: <221s NAME/KEY: MOD RES <222s. LOCATION: (1) . . (1) 223 OTHER INFORMATION: D-Ala 22 Os. FEATURE: <221s NAME/KEY: MOD RES <222s. LOCATION: (3) ... (3) <223> OTHER INFORMATION: Cyclohexyl-Ala 22 Os. FEATURE: <221s NAME/KEY: MOD RES <222s. LOCATION: (13) . . (13) 223 OTHER INFORMATION: D-Ala

<4 OOs, SEQUENCE: 4

Ala Lys Ala Val Ala Ala Trp Thir Lieu Lys Ala Ala Ala 1. 5 1O

<210s, SEQ ID NO 5 &211s LENGTH: 5 212. TYPE: PRT <213> ORGANISM: Artificial Sequence 22 Os. FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide

<4 OOs, SEQUENCE: 5

Ser Lys Llys Llys Llys 1. 5 US 2014/0220079 A1 Aug. 7, 2014

- Continued

<210s, SEQ ID NO 6 &211s LENGTH: 9 212. TYPE: PRT <213> ORGANISM: Artificial Sequence 22 Os. FEATURE: <223> OTHER INFORMATION: Description of Artificial Sequence: Synthetic peptide

<4 OOs, SEQUENCE: 6 Gly Asp Pro Llys His Pro Llys Ser Phe 1. 5

What is claimed is: 3. The method according to claim 1, wherein the first 1. A method for treating a cancer in a Subject, which com cellular immunity induction prompter is a helper peptide. prises mucosally administering a cancer vaccine composition 4. The method according to claim 1, wherein the first comprising: cellular immunity induction prompter is a combination of a (i) a HER2/neu E75 peptide and/or a modified HER2/neu helper peptide and at least one Substance selected from the E75 peptide; and group consisting of a TLR ligand, a cyclic dinucleotide, an (ii) a first cellular immunity induction prompter selected immunomodulatory Small molecule drug, a cyclooxygenase from a TLR ligand, a cyclic dinucleotide, a helper pep inhibitor, a prostaglandin receptorantagonist, a prostaglandin tide, an immunomodulatory Small molecule drug, a receptor agonist, a TSLP production inhibitor, an adenylate cyclooxygenase inhibitor, a prostaglandin receptor cyclase inhibitor, an omega-3 fatty acid, a PPAR agonist, a antagonist, a prostaglandin receptor agonist, a TSLP dopamine receptor antagonist, a dopamine receptoragonist, a production inhibitor, an adenylate cyclase inhibitor, an histamine receptoragonist, a histamine receptor antagonist, a omega-3 fatty acid, a PPAR agonist, a dopamine recep serotonin receptoragonist, a serotonin receptor antagonist, a tor antagonist, a dopamine receptor agonist, a histamine vasopressin receptor antagonist, a vasopressin receptor ago receptoragonist, a histamine receptor antagonist, a sero nist, a muscarine receptor antagonist, a muscarine receptor tonin receptoragonist, a serotonin receptor antagonist, a agonist, an adrenaline receptor antagonist, an adrenaline vasopressin receptor antagonist, a vasopressin receptor receptor agonist, an angiotensin receptor agonist, a GABA agonist, a muscarine receptor antagonist, a muscarine receptor agonist, a thrombin receptor antagonist, a thrombin receptor agonist, an adrenaline receptor antagonist, an receptoragonist, an opioid receptoragonist, an ADP receptor adrenaline receptor agonist, an angiotensin receptor agonist, a leukotriene receptor antagonist, a leukotriene agonist, a GABA receptor agonist, a thrombin receptor receptoragonist, a melatonin receptoragonist, a Somatostatin antagonist, a thrombin receptoragonist, an opioid recep receptor agonist, a cannabinoid receptor agonist, a sphin tor agonist, an ADP receptor agonist, a leukotriene gosine-1 phosphate receptor agonist, a metabotropic receptor antagonist, a leukotriene receptor agonist, a glutamate receptor agonist, a phospholipase A2 inhibitor, a melatonin receptoragonist, a Somatostatin receptorago nist, a cannabinoid receptor agonist, a sphingosine-1 TGF-B production inhibitor and a Th2 cytokine inhibitor. phosphate receptor agonist, a metabotropic glutamate 5. The method according to claim 1, wherein the cancer receptoragonist, a phospholipase A2 inhibitor, a TGF-B vaccine composition is in the form of a film preparation. production inhibitor, a Th2 cytokine inhibitor, and com 6. The method according to claim 1, wherein the cancer binations of two or more kinds thereof to the subject. vaccine composition is in the form of a liquid formulation. 2. The method according to claim 1, wherein the cancer vaccine composition further comprises a second cellular 7. The method according to claim 1, wherein the cancer immunity induction prompter that is a pharmacologically vaccine composition is in the form of an orally-disintegrating acceptable acid or a pharmacologically acceptable salt tablet for mucosal administration. thereof. k k k k k