Peptide Vaccines for Cancer Therapy

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Send Orders for Reprints to [email protected] 38 Recent Patents on Inflammation & Allergy Drug Discovery 2015, 9, 38-45 Peptide Vaccines for Cancer Therapy

Daniela Cerezo, María J. Peña, Michael Mijares, Gricelis Martínez, Isaac Blanca and Juan B. De Sanctis*

FOCIS Center of Excellence, Instituto de Inmunología, Facultad de Medicina, Universidad Central de Venezuela, Caracas, Venezuela

Received: October 13, 2014; Accepted: January 21, 2015; Revised: January 24, 2015

Abstract: For around four decades, vaccines of different kinds have been developed to treat different types of cancer. However, promising results encountered in the early phase contrasted with the results recorded in clinical studies. Recent discoveries in the vaccine field, adjuvants and delivery systems, and antigen presentation have lead to new patented approaches. The current review is focused on general description of peptide vaccines involving cancer antigen presentation, specific immune response, cell death dependent pathways, and target therapy for modified or mutated oncogenes. A rapid evolving research in the area may evolve in fruitful outcomes in the near future. Keywords: Adjuvants, antigen presentation, cancer, immune response, peptide, vaccines.

INTRODUCTION antigens generated through nonstandard transcriptional and translational mechanisms may also be presented by MHC-I The key issue in inducing immune response is antigen [2-5]. presentation [1]. Antigen presentation is a complex process that involves intracellular compartments with a sequence of Antigen presentation by tumor cells is different from nor- events from degradation of a complex pathogen, or cell up to mal cells and therefore analysis of tumor antigens and cryptic binding to major histocompatibility complex proteins (MHC) tumor antigens differs enormously between them [2-5]. Ex- class I (MHC-I) or class II (MHC-II). Antigen presentation perimental data have revealed that tumor antigens are ex- generates a specific response, cytotoxic, MHC-I, antibody, T pressed differently (enhanced amount of antigen, novel neo helper response and, MHC-II [1]. The protective specific epitopes, etc.) as compared to normal cells [2-5]. In some tu- anti-tumoral immune response involves cytotoxic T cells and mors, the use of docking models, based on the data generated consequently MHC-I presentation [2-5]. However, immune from different MHC-I and relevant tumor-specific antigens response against tumor involves also the other T cell sub- (TSA) or tumor-associated antigens (TAAs), has revealed a populations [3-5]. probability cluster [2-5]. This cluster refers to binding and possible in vivo response [5]. Despite this fact, novel and The peptides presented by MHC-I vary from 8 to 11 highly immunogenic epitopes, capable of inducing an effec- amino acids in length and are generated from the proteaso- tive anti-tumor response, are not easily encountered [2-5]. In mal degradation of cytosolic protein antigens that are taken addition, adjuvants and delivery systems used in vaccines may up by the endoplasmic reticulum (ER) and consequently modulate antigen presentation by antigen presenting cells re- loaded onto MHC-I molecules [1-5]. Once the peptide binds sulting in a decrease in effective anti-tumor response or an to MHC-I, in the ER, it stabilizes the complex which is then increase in tolerogenic response. Thus, therapeutic cancer vac- transported to the cell membrane [1-5]. In the membrane, the cines have been proposed as a result of analyzing the wide peptide can be scrutinized by circulating CD8 cells, a proc- variety of genetic mutations and abnormal protein expressions ess usually named “immune surveillance” [2-5]. Since encountered in different tumors [2-5]. Its major drawback in- MHCs are highly polymorphic, the binding of the antigen volves the limited expression of the antigen and the highly and its presentation is not universal [2-5]. There are certain probability of mutation depending on the stage and type of “public” MHC-I proteins which are predominantly expressed tumor [2-5]. In addition, tumor microenvironments induce in different ethnic groups and thus serve as the target mole- tolerogenic responses and ideally, but it is not always encoun- cules for therapeutic vaccines [2-5]. Nonetheless, cryptic tered; adjuvants, peptides and immune enhancers should be able to surpass the tolerogenic response [4, 5]. *Address correspondence to this author at the Instituto de Inmunología, The aim of the present review is to give a brief picture of Facultad de Medicina, Universidad Central de Venezuela, Apartado 50109, Caracas 1050-A, Venezuela; Tel: +58-212-6934767; peptide vaccines in cancer therapy and the new patents that Fax: +58-212-6932815; Email: [email protected] have been submitted in the recent years.

TUMOR ANTIGENS culated epitopes could bind multiple HLA A3 alleles in the superfamily, suggesting that these peptides could overcome Many groups of researchers have tried to understand if some differences in HLA expression in patient to patient the usually hampered immune response against a tumor is comparisons [3]. Algorithmic models also fail to provide the due to the lack of recognition of the abnormal cells or im- only specific interaction since antigen binding may be re- mune tolerance. In order to address this issue, an overview of corded to other MHC molecules with different affinity [3]. the different approaches used is presented. One may envision that algorithmic models may represent The first lesson that the researchers have learned is that partially what occurs in vivo, and possibly the direct assess- tumor antigen expression is heterogeneous [3]. There are ment of cytotoxic cells in the tumor would give more spe- tumor specific and associated antigens [2-5]. Moreover, sev- cific results [3, 5]. eral levels of expressions of these antigens may be encoun- Studies with HPLC and mass spectroscopy of the MHC-I tered back as: 1) lack of antigen; 2) low amount of antigen; peptide complex are able to validate the predictive models 3) high amount of antigen; and 4) homogenous and/or het- and generate new possible targets [3, 5, 8-10]. Immunopro- erogeneous antigens (mixed or combined antigens). Conse- teomic analysis represents an enormous advantage due to the quently, it is not a simple task to find the ideal antigen to fact that epitopes that are naturally presented on tumor cells which the immune response should be directed. surface correspond to the clinically important targets for The first approach in cancer vaccines was to homogenize immunotherapy and vaccine design [3, 5, 8-10]. Moreover, tumor cells in order to assess specific antigens [2-5]; how- cancer neoepitopes should be addressed consciously [9]. ever, this approach and the use of vaccine with and without These identification techniques permit subtract antigens pre- adjuvants and immune enhancers resulted in a lack of spe- sented in normal tissue leading to only relevant molecules cific responses and a high amount of unwanted secondary for cell activation. Several models, including an in silico effects. The proteomic analysis and comparisons of normal model predicting peptide epitopes and vaccines have been and tumor cells were, in most cases, difficult to accomplish. published [8-11]. An alternative approach to tumor homogenates was the The important issue is to ascertain the real epitopes to use of cDNA libraries of tumor cells and subsequently trans- which the vaccine should be designed, the construct, adju- fect them into normal, antigen presenting cells [3-5]. By this vant, immune enhancer and the delivery which would lead to approach, translated antigens are processed and presented as the ultimate goal, an effective immune response against the epitopes loaded in MHC-I molecules. This technique is use- tumor. ful for MAGE-1, melanoma antigen, presented by HLA-A1, tyrosinase presented by HLA-A2, and other antigens [3-5]. CANCER PEPTIDE VACCINES Nevertheless, the processing of the tumor antigen does not Several reviews have addressed the issue of different necessarily resemble real in vivo antigen presentation since vaccines assays, clinical trials and their outcomes [3-5, 12- transcription of the antigen may be modulated differently in 15, http://www.clinicaltrials.gov]. The current review gives tumor cells as compared with normal cells [3-5]. There may only a general overview of the most important up to date be over or under expression of the antigen plus the posttran- approaches which are summarized in Tables 1 and 2. scriptional modifications may differ among tumor versus As aforementioned, most of the peptide vaccines were normal cells [3]. Skipper and co-workers [6] showed the developed with prediction motif methodology. Using this difference in CD8 response to tyrosinase tumor antigen in technique, the most studied models involved melanoma and vivo and the aforementioned technique. Fortunately, a renal carcinoma. The first clinical trial implicated the protein change in amino acid, an asparagine to aspartic acid, did not MAGE 1 (melanoma associated antigen). The results of im- affect HLA-A2 binding and generated a robust T cytotoxic munoproteomic assessments involved multiple epitopes [2-5, response. With several other antigens, the response was ei- 8]. The first interesting report dealt with the effectiveness of ther deem or nonexistent [3]. Proteolytic activity, involved in a 12 versus a 4 MHC-I peptide-based vaccine, a Phase II trial antigen presentation, may also be responsible for this differ- with stage IIB to IV melanoma patients [16]. Even though, ence [3-5]. no significant clinical results were recorded; the production Another method to identify tumor antigens is motif pre- of IFN was increased in cytotoxic cells and consequently, diction using pMHC-I binding algorithms [3-5]. The model the vaccine was able to generate a cytotoxic response to the involves sequences of peptides that bind MHC-I that can be inoculated antigens [16]. Then, new multi-epitope vaccines cleaved by the proteasomal complex. Using this prediction were designed to overcome antigen loss or generation of new model, Fisk and coworkers [7] were able to identify nineteen epitopes were designed [2, 3-5, 8-11]. different candidates for Her-2 binding to HLA-A2. However, Slingluff and co-workers [17] evaluated, in a randomized only one of the nineteen candidates was able to generate a phase II clinical trial, the effectiveness of 12 versus 4 MHC-I good cytotoxic response in vitro [7]. For other antigens such peptide based vaccines. Even though, the vaccine that con- as carcinoembrionic antigen (CEA) and Her-2/neu, the cal- tained 12 peptides along with tetanus helper peptide, GM-CSF 40 Recent Patents on Inflammation & Allergy Drug Discovery 2015, Vol. 9, No. 1 Cerezo et al.

Table 1. Table 1 Represent the Different Strategies Involved in Cancer Peptide Vaccines.

Strategy Characteristics General Conclusions

Tumor tissue ho- Homogenate inactivated or modified. Freund’s Lack of specific antigens. Important side effects. No or low response mogenate adjuvant

Genomic library of Expression of antigens in normal target cells Specific tumor antigens. Amount of antigen expression in vivo unknown. New tumor cells specific epitopes. Autoimmune response avoided

Autologous tumor Peptide vaccine constructed from patient’s Good CD4 and CD8 response in haematological tumors early phase. Moderate antigens own tumor to good response depending cancer type and vaccine construct

Immune- Use of models for antigen construction and Good cytotoxic T cell activation, but no clinical improvement binding to MHC-I Proteomic/

docking analysis

Antigen extracted Analysis of in vivo response. Analysis of Classification of prevalent antigen for cytotoxic response HLA specific from CD8+ cells Tumor associated and Tumor specific antigens peptide binding to specific HLA. Moderate response depending on the vaccine construct

Antigenic peptides for Use of specific peptides for both HLA types Activation of CD4 and CD8 specific cells against the tumor. Peptide binding to HLA Class I and specific HLA. Moderate to good response depending on vaccine construct Class II

Chaperone protein General immunogenic responses to tumor Activation of CD4 and CD8 cells against the tumor. with tumor antigens antigens using know antigenic protein Moderate to good response depending cancer type and vaccine construct

Activated Dendritic Antigen presentation by DC using antigen Good activation of CD8 cells in vivo cells with glycan ligands, antibodies to endocytic Moderate to good response depending on vaccine construct receptors. Anti T cell inhibitory receptors

Table 2. Table 2 is a Complement of Table 1 Involving Strategies in Cancer Vaccines. Other Strategies Used in Cancer Peptide Vaccines.

Strategy Characteristics General Conclusions

Her-2 as antigen Target Her-2 expressing tumor Activation of CD4 and CD8 cells against the tumor. Decrease tolerance

Moderate to good response depending on cancer type and vaccine construct

Mutated ras as Target pharmacological resistant ras Decrease tumor survival. Awaiting clinical trials antigen

VEGF, VEGF R1 as Block tumor vascularisation class I/II specific Decrease tumor burden. Moderate to good response depending on cancer type target peptides and vaccine construct

Cell cycle inhibition Antibodies to mutated p53, cyclin b-1 Combination with antigenic peptides. Good results in colon cancer. Expecting results for other type of cancer

Target inhibitors of Survivin as target for tumor cells apoptosis Induction of apoptosis in resistant tumor cells. Effective clearance of the tumor apoptosis pathway resistant Moderate to good response depending cancer type and vaccine construct

Induction of auto- Use of inductor of autophagosome plus pep- Decrease in tumor burden by therapy or autophagosome activator. Enhancement phagy and immune tide vaccine of immune response with cancer peptide vaccine. No clinical trials documented response

Target regulatory T Use FoxP3 as antigen to decrease regulatory T Preliminary results: Decrease of regulatory T cells, non specific. The vaccine cells cells near tumor should be combined with other peptide antigens Cancer & Peptide Vaccines Recent Patents on Inflammation & Allergy Drug Discovery 2015, Vol. 9, No. 1 41 and Montanide ISV-51, induced a strong CD8 response (high In different clinical trials, there have been several ways IFN production and response), no major clinical benefit was by which peptides and vaccines are administered. Intrader- recalled as compared with the mixture containing 3 peptides mal, intratumor and subcutaneous routes have been used combined with Montanide ISV-51 and containing either depending on the vaccine composition and tumor character- GM-CSF, IFN2b, or both [17]. The preparation with 12 istics [24, 25]. The aim of this route is to reach the lymph peptides, however, was safe and there was no competition nodes through the traditional antigen presenting cells in or- among peptides for MHC-I presentation. Kirkwood et al. der to generate a marked, non tolerogenic, immune response. [18] analyzed the data from 115 vaccinated patients with One of the current hypotheses refers that follicular dendritic stage IV melanoma and showed that T cell activation upon cells are key players of tumor antigen presentation and, con- peptide presentation (defined by IFN- secretion), correlated sequently, involved in an effective anti-tumor response [26, with an increase in survival rate. Addition of cytokines to 27]. this vaccine preparation does not increase, rather it may de- Dendritic cell activation has been used in different cancer crease, the number of circulating CD4 and CD8 cells [19]. vaccine models. The initial ex vivo models of antigen prim- These results contrast with the increase in regulatory T cell ing and reinfusion to the patient were promising but expen- numbers [19]. sive [26]. The other interesting condition was to use antibod- Since CD4 activation may potentiate CD8 cytotoxic re- ies directed against endocytic receptors on the surface of the sponse, several authors have added CD4 activating peptides DCs or against inhibitory molecules in order to cross activate in the vaccine preparation [3, 13-14]. Slingluff et al. 2013 dendritic cells for optimal response, and finally, the use of [20], compared CD4+ and CD8+ T cell responses in 175 glycan ligands for dendritic cell receptors [28, 29]. Antibod- patients with stage IV melanoma after inoculation of: 1) a 12 ies against T cell inhibitory receptors, PD-1 and CDTA4 or peptide MHC-I restricted vaccine alone; 2) the aforemen- activating ligands CD154, enhance immune response in in- tioned vaccine combined with either a) tetanus peptide, or b) tra-tumor vaccines [28, 29] suggesting that targeted dendritic with 6 melanoma helper epitopes; and 3) a vaccine contain- cells near the tumor may be able to efficiently present the ing only 6 melanoma MHC-II helper epitopes. No increase specific antigen, while blocking the tolerogenic response in survival rate, despite CD8+ activation, in groups 1 and 2 associated dendritic cells close to the tumor. Thus, the were observed. On the other hand, the vaccine that contained aforementioned combination would enhance specific im- melanoma-specific helper peptides was associated with an mune response against the tumor and overcome tolerance. increase in survival rate [20]. Thus, an optimal activation The use of immune enhancers as Montanide, along with response of CD8+ and CD4+ cells rather than only the as- GM-CSF, chaperone proteins (heat shock proteins) has been sessment of CD8+ cell number and cytotoxic activity only partially successful in colon and breast cancer with CEA and seems to be more illustrative of in vivo effect of the vaccine. Her-neu [3, 11, 30]. Again, IFN is induced upon vaccina- Several researches researchers have shown that dendritic cell tion, but the clinical responses are not as strong as expected. activation induced optimal responses to vaccines using HLA- In order to enhance an effective clinical response, several A2 and HLA-A24 melanoma specific peptides [21, 22]. groups constructed vaccines in which tumor cells would de- Even though the results are modest, an interesting new area crease its replication or, on the contrary, enhance cell death of research has started using this approach which includes in by activating apoptosis and autophagosome pathways [31- the route of administration [23]. 40]. Taking into account that most of the used chemotherapy Several other approaches involving TAA and TSA for would, as the main goal, affect the aforesaid pathways the tumor peptide vaccine therapy (reviewed in [3]) were de- clinical response may increase substantially. signed to attack several targets: 1) vascular endothelial In order to overcome T regulatory cell generation and growth factor receptor 1 (VEGFR1) for several cancers; 2) induce autophagosome formation, Walter et al. [31] planned indoleamine 2, 3 dioxygenase (IDO) for HLA-A2+ lung in a vaccination scheme, involving renal cell cancer patients. cancer patients; 3) glypican-3 peptides for hepatocellular The authors constructed a vaccine with nine HLA-A2 re- carcinoma; and 4) multiepitope vaccines for ovarian and stricted peptides retrieved by immunoproteomic assays, and breast cancer, prostate cancer, and biliary tract cancer. The injected intradermal with IMA901 and GM-CSF after treat- combination therapy was useful, as described in melanoma ing the patients with cyclophosphamide 3 days prior the in- assays, and in several models. The results encountered so far oculation. Cytotoxic T cell responses to the used antigens are promising [3]. were associated with limited disease and prolonged survival [31]. The survival rate was due to a decrease of T regulatory One of the other issues analyzed is how the vaccine cells in the tumor microenvironment. Several other important should be administered. This is a major issue since, depend- elements in the vaccine construct have been proposed [32]. ing on the route, antigen presentation may be impaired, and antigens may be either lost or not efficiently presented. The Cell cycle inhibition, apoptosis or autophagosome induc- adjuvants used in the vaccine design also condition the ad- ers have also been used in combination with peptide vaccines ministration of the vaccine. Consequently, vaccine design for [33]. Mutated p53, present in several tumors, cyclin B1 as cancer therapy is not an easy task. well as other kinases that regulate cell cycle appear to be 42 Recent Patents on Inflammation & Allergy Drug Discovery 2015, Vol. 9, No. 1 Cerezo et al. interesting targets for tumor growth inhibition which would Adjuvants and Delivery Systems facilitate immune eradication [33]. Several vaccines have Adjuvant and delivery systems are important elements in been generated against p53 [34, 35]. Moreover, protein apop- the efficiency of vaccines [47]. The use of new adjuvants and tosis inhibitors like survivin would also enhance tumor sur- emulsions has been useful for other vaccines for infectious vival and are, along with p53 mutated, and are useful target diseases [47]. A group of different adjuvants has been used for cancer therapy; several vaccines have been directed to and tested in clinical trials [10]. The use of chaperone pro- surviving and its mutated counterparts [36-38]. teins and other ligands of Toll receptors and PAMP receptors Tsuruma and co-workers [37] assessed the effect of sur- have promising results [3, 10, 46-48]. One of the used is a vivin peptide vaccine with or without Montanide ISA-51 in a non-emulsion vaccine delivery formulation DepoVax™ phase I trial of patients with breast cancer. Even though in (DPX) which has been an effective inductor of cytotoxic this trial the clinical response was not as expected, the results responses in ovarian, breast or prostate cancer [49, 50]. served for generating new approaches for compound vac- Nanoparticles and Nano emulsions [51], even though incipi- cines using other adjuvants. More recently, Lennerz [38] ent, have been proposed for intratumor delivery of antigens showed interesting results in patients with solid tumors. and for the use of monoclonal antibodies against inhibitory Comparing the good results reported by Kameshima and molecules [27, 28]. Even though the scope of the review is collaborators [39] with colon cancer patients treated with a not to document the different new adjuvants, delivery sys- mixed vaccine that contained Montanide, IFN- and cancer tems and immune enhancers, the aim of giving a brief outline and survivin peptides, with those of Zeestraten et al. [40] of subject is to alert the reader that vaccine therapy draw- that involved a mixture of long p53 peptide and IFN-, the backs may not be due to the peptide used but due to the other inhibition of cell cycle and apoptosis induction are critical in components of the vaccine. this type of cancer. Most probably, the constructs and a RECENT PATENTS combination of both (up to date no reports of the combination have been published) are efficient in reducing tumor There have been a lot of new developments in the field burden and enhance immune response. which, of course, need to be tested in clinical trials accord- An important element is involving several other targets ingly. The majority of the patents involve peptide composi- VEGF, her-2, her-2/neu, Wilms' tumor gene 1 (WT1) which tions, most of them activate MHC-I and II, are either di- may benefit more than one cancer type [41-43]. Among rected to specific proteins endogenous or not and/or inhibi- other good targets is the use of vaccines against mutated ras tors of different cell pathways. oncogene which would decrease tumor resistance to chemo- Several peptides have been patented for specific or from therapy [44]. Several examples of TAA and TSA for tumor treatment of combined cancers. In order to take general ex- peptide vaccine therapy (reviewed in [3]) involve 1) vascular amples, Kudo and Kawami [52] developed two peptides endothelial growth factor receptor 1 (VEGFR1) for several form a snail protein conferring immune response against cancers, 2) indoleamine 2, 3 dioxygenase (IDO) for HLA- tumors. Itoh and Yamada [53] constructed a vaccine with 6 A2+ lung cancer patients; 3) glypican-3 peptides for hepato- to 13 peptides derived from tumor antigens which potentially cellular carcinoma; and 4) multiepitope vaccines for ovarian generate broad immune response against tumors, based upon and breast cancer, prostate cancer, biliary tract cancer. a previous patent on personalized tumor peptides [54]. Using Several researchers [3, 45] have postulated that personal- several different analogies, numerous amounts of peptides ized vaccine as a good approach for cancer vaccines. Proba- have been patented based on the special type of tumor, re- bly, combined vaccine schemes could enhance anti-tumor sults from trial using personalized cancer peptide vaccines as responses. well as other approaches [55-71]. However, no published clinical trials of these patents, at least to our knowledge, Other interesting approaches are the carbohydrate moie- have shown to be effective although all the authors claimed ties present in the tumor. Carbohydrate molecular mimicry that their constructs enhance immune response against tu- [46] has been used to enhance immunogenic properties of mors. glycan peptides in tumor cells plus an enhancement of peptide epitopes for cancer cells. In addition, conformational Other patented approaches involved specific tumors. In analysis and deconvolution analysis of glycan proteins ex- haematological tumors, a complex peptide approach [71] that pressed in tumor cells has reveled new possible targets. One involves leukaemia, lymphoma and myeloma was proposed. example is the mucin family of proteins and its glycan back- The vaccine is supposed to generate an effective immune bones that seem to differ depending on the cancer type and response against different types of tumor. The hypothesis stage. It has been shown [46] that mucin proteins, in general, that undifferentiated tumor should be the target is gaining are not drastically modified in tumor tissue but rather its car- supporters since the blockage of tumor and metastasis could bohydrate moiety varies, including circulating antibodies be obtained in certain models. against the glycan protein can be observed in cancer patients. A lot of effort has also been involved in generating opti- Thus, it is an interesting idea to merge peptides and carbohydrate to build an effective vaccine for cancer therapy. mal vaccines against Wilms tumor 1 antigen, WT1 [72-75]. Cancer & Peptide Vaccines Recent Patents on Inflammation & Allergy Drug Discovery 2015, Vol. 9, No. 1 43

WT1 peptides seem to induce an efficient and sustained im- New immune stimulants have been proposed, some of them mune response. Other patents have dealt with combination are already known as part of the polysaccharide from infec- therapy [76] and vaccine administration [77, 78]. The ther- tious agents, used in influenza and patented years ago, and apy has been shown to be effective and the results of clinical other are new compounds metallic compounds in similar trials should be published in the near future. fashion as aluminium salts used as adjuvants for more than 100 years. In order to increase the effectiveness of treatment in difficult to treat cancers, new tissue targets and cryptic antigens CURRENT & FUTURE DEVELOPMENTS have been assessed. New targets for breast cancer have been documented and There have been numerous studies on cancer. Unfortu- involve: -lactalbumin, S1 casein, -casein and -casein. nately, most of them have not been successful. One may as- Two patents have been designed involving polypeptides of sume that, in clinical trials, the types of patients that are in- all four aforementioned proteins [79], and the other involv- volved are complex, often treated with several therapies and ing only -lactalbumin [80]. It would be interesting to design are partially immune deficient. It follows then that the results complex trial involving also the new peptide for HER onco- of the clinical trials are difficult to standardize. Despite this genes [81]. fact, new approaches have been promising; increased patients’ survival, and decrease tumor burden have been re- Insulin-like growth factor (IGF) is involved in tumor corded. Future assessments may facilitate new therapies or microenvironments in several solid tumors [82]. Birne [83] combinations. disclosed a vaccine comprising a pappalysin which is a met- alloproteinase that specifically cleaves IGFBP-4 and IGFBP- Combined peptides, able to present specific antigens 5, resulting in release of bound IGF. Some groups have been along with inhibition of cell pathways, cell cycle or inhibitor searching for different forms to inhibit extracellular matrix receptors, along with efficient antigen presentation represent formation that is involved in tumor growth [82], thus, future the new promising therapeutic vaccine. Further research in patents may involve other enzyme such as hyaluronidases, adjuvants, delivery systems, and nanotechnology may also chondroitinases, etc. enhance effectiveness of vaccine therapy. The construct which involves more than one antigen recognized by differ- The IL-13 2 receptor has also been targeted in peptide vaccines for brain cancer [84] and ovarian cancer [85]. In ent MHC as well as more general tumor antigens would en- ovarian cancer, however, the combination used was the hance vaccine therapy which, at the end run, may be the polypeptide that includes mesothelin, HER-2/neu, IL-13 re- most simple and effective way to induce an effective anti- ceptor 2, survivin, CD133, gp100, AIM-2, and epidermal tumor immune response. growth factor receptor (EGFR) [85]. The interesting element There is still a long way to go in cancer therapy and the is that blocking IL-13 would decrease the anti-tumor re- increase in tumor incidence in the population should alert the sponse of the surrounding cells and consequently enhances authorities so as to promote new and simple approaches to the response against the tumor. In parallel, a patent against decrease the prevalence of this terrible disease. Hopefully, a Foxp3 was also presented with the scope to decrease T regu- bright future is near than expected. latory cells nearby the tumor [86]. The decrease in T regulatory cells has been shown to benefit immune response and CONFLICT OF INTEREST decrease tumor burden. The authors confirm that this article content has no con- Along with the use of generation of new patented vac- flict of interest. cines involving cyclin [87] and p53 [88] have complemented previous efforts to overcome the number of mutations in- ACKNOWLEDGEMENTS volved in different cancer that promote tumor growth and The work was partially supported by grant by the Vene- resistant to chemotherapy. zuelan foundation of scientific research (FONACIT) project The use of vaccines against endogenous virus has also G2005000389, by the Research Coordination of the Faculty been addressed. Herpes virus proteins as well as other viral of Medicine of the Venezuelan Central University, Caracas proteins codified in the genome could be responsible for Venezuela. oncogenes activation, and thus for tumor promotion and The authors want to dedicate the present issue to the growth. An interesting patent has been developed [89]. In the twenty fifth anniversary of the Institute of Immunology in near future, other patented compounds or inhibitors of en- Caracas, FOCIS centre of Excellence. dogenous oncogenes could be important for tumor control. Finally, other vaccines have taken into account changes REFERENCES in frame shift generally recorded in cancer proteins [90, 91] [1] Newell EW. Higher throughput methods of identifying T cell epi- and glycan moieties [92-94] both of which have been highly topes for studying outcomes of altered antigen processing and pres- documented in the literature, but generally not addressed. entation. Front Immunol 2013; 4: 430. 44 Recent Patents on Inflammation & Allergy Drug Discovery 2015, Vol. 9, No. 1 Cerezo et al.

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