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Preclinical Development of Hivax: Human Survivin Highly

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Preclinical Development of Hivax: Human Survivin Highly RESEARCH PAPER Human Vaccines & Immunotherapeutics 11:7, 1--11; May 1, 2015; © 2015 Taylor & Francis Group, LLC Preclinical development of HIvax: Human Survivin Q1 Highly Immunogenic vaccines Peter R Hoffmann1, Maddalena Panigada2, Elisa Soprana2, Frances Terry3, Ivo Sah Bandar4, Andrea Napolitano5, Aaron H Rose1, Fukun W Hoffmann1, Lishomwa C Ndhlovu4, Mahdi Belcaid6, Lenny Moise7, Anne S De Groot7, 5 Michele Carbone5,8, Giovanni Gaudino5, Takashi Matsui9, Antonio Siccardi2, and Pietro Bertino1,* 1Department of Cell and Molecular Biology; John A. Burns School of Medicine; University of Hawai’i; Honolulu, HI USA; 2San Raffaele University and Research Institute; Milano, Italy; 3EpiVax, Inc.; Providence, RI USA; 4Department of Tropical Medicine; John A. Burns School of Medicine; University of Hawai’i; Honolulu, HI USA; 5University of Hawai’i Cancer Center; University of Hawai’i; Honolulu, HI USA; 6Hawai’i Institute of Marine Biology; University of Hawai’i; Honolulu, HI USA; 7Institute for Immunology and Informatics; University of Rhode Island; Providence, RI USA; 8Department of Pathology; John A. Burns School of Medicine; University of Hawai’i; Honolulu, HI USA; 9Department of Anatomy; Biochemistry 10 and Physiology; John A. Burns School of Medicine; University of Hawai’i; Honolulu, HI USA Keywords: cancer vaccines, EpiMatrix, fowlpox, immunodominant epitopes, mesothelioma, T-Lymphocytes, tregitopes Our previous work involved the development of a recombinant fowlpox virus encoding survivin (FP-surv) vaccine that was evaluated for efficacy in mesothelioma mouse models. Results showed that FP-surv vaccination generated significant immune responses, which led to delayed tumor growth and improved animal survival. We have extended 15 those previous findings in the current study, which involves the pre-clinical development of an optimized version of FP- surv designed for human immunization (HIvax). Survivin-derived peptides for the most common haplotypes in the human population were identified and their immunogenicity confirmed in co-culture experiments using dendritic cells and T cells isolated from healthy donors. Peptides confirmed to induce CD8C and CD4C T cells activation in humans were then included in 2 transgenes optimized for presentation of processed peptides on MHC-I (HIvax1) and MHC-II 20 (HIvax2). Fowlpox vectors expressing the HIvax transgenes were then generated and their efficacy was evaluated with subsequent co-culture experiments to measure interferon-g and granzyme B secretion. In these experiments, both antigen specific CD4C and CD8C T cells were activated by HIvax vaccines with resultant cytotoxic activity against survivin-overexpressing mesothelioma cancer cells. These results provide a rationale for clinical testing of HIvax1 and HIvax2 vaccines in patients with survivin-expressing cancers. 25 Introduction Survivin has been shown to fulfill major criteria for prime tar- 45 get antigens included in broad applicable anti-cancer vaccines: 1) Despite recent progress in surgical, chemotherapeutic, and tumor cells depend on its actions for survival or proliferation, 2) radiotherapy approaches, several cancers are still difficult to expression is strong in multiple tumor types but rarely detectable treat and cure, especially in patients with advanced stages of in normal tissues, 3) immunogenicity has been demonstrated in the disease. Therefore, new therapeutic strategies are needed patients with different cancers, and 4) peptides restricted by dif- 50 30 and immunotherapeutic approachestargetingtumor-associated ferent HLA molecules are known. Survivin is expressed in a antigens (TAAs) are among the most prominent approaches majority of tumor cells at all stages, from premalignant to meta- recently developed. CD8C cytotoxic T lymphocytes (CTLs) static lesions, in solid tumors and haematopoietic malignancies, are the most important effector cells for antitumor immune and the gene encoding survivin is the fourth most abundantly responses. CTLs recognize TAA-derived peptides that are pre- expressed gene in melanomas and cancers of the colon, lung, 55 35 sented on the tumor cell surface in association with major his- brain, and breast.6-8 Expression of survivin is typically limited to tocompatibility complex (MHC) class I molecules, leading to developing tissues but becomes reactivated in adult tissues during 1 tumor cell killing. CD4C Thelpers(Th)cellsprovideassis- the neoplastic transformation, contributing to apoptosis evasion tance to CTLs in the form of soluble mediators like cytokines, and molecular pathways driving unrestricted proliferation and which enhance the CTL expansion and cytolytic function.2 angiogenesis in tumor cells.9 Survivin expression is a marker of 60 40 Initial activation of na€ıve antigen-specific lymphocytes is poor prognosis and/or resistance to therapy in multiple cancers.10 mediated by specialized MHC-positive cells, particularly den- In patients with a variety of cancers, survivin-specific cell medi- dritic cells (DC). Clinical evidence for the effectiveness of ated and humoral immune responses have been shown.11-14 Pre- antitumor immune responses has been obtained in several clinical and clinical data from survivin vaccination studies clinical settings.3-5 suggest that these vaccines can induce immune responses and do 65 *Correspondence to: Pietro Bertino; Email: [email protected] Q2 Submitted: 04/14/2015; Accepted: 05/07/2015 http://dx.doi.org/10.1080/21645515.2015.1050572 www.tandfonline.com Human Vaccines & Immunotherapeutics 1 not raise substantial safety concerns. Multiple HLA class I-bind- these, 4 sequences, positively scored for the considered alleles, ing peptides and one HLA class II-binding peptide of survivin were selected for experimental validation (Table S1). For Class 120 have been identified, some of which have demonstrated immuno- II, epitope dense regions containing sequences predicted to bind genicity in clinical trials.15,16 multiple Class II HLA alleles (DRB1*0101, *0301, *0401, 70 Malignant mesothelioma (MM) is an aggressive and deadly *0701, *1101, *1301 and *1501) were also identified. Three of cancer. It originates from a chronic inflammatory process arising these regions containing “hits” for several analyzed alleles were from asbestos or erionite exposure. The median patient survival selected and the resulting peptide sequences were synthesized for 125 is 9–12 months from diagnosis and intervention with trimodality experimental validation (Table S2). therapy (chemotherapy, surgical resection and thoracic radiation) 75 only extends survival by an average of 5 months. Survivin overex- Human survivin-derived peptides induce activation of 17,18 pression has been reported in MM in different studies. Our primary human CD3C T cells previous work involved the development of a novel recombinant Seven peptides (Hsurv1–7) representing sequences considered fowlpox virus encoding survivin (FP-surv) vaccine that was evalu- immunogenic in a major number of alleles were synthesized 130 ated for efficacy in different MM mouse models. Mice were (Table 1). These EpiMatrix predicted peptides were used to 80 injected subcutaneously or intraperitoneally with murine fiber- prime human DC from na€ıve healthy donors. Autologous T cells induced MM tumor cells and vaccinated with FP-surv. Results were co-cultured with the DC for a 2 wks period, followed by showed that FP-surv vaccination generated significant immune reactivation with DC loaded with the same peptide in the pres- responses in both models, which led to delayed tumor growth ence of monensin, to allow evaluation of IFNg production. All 135 and improved animal survival.17 peptides but one (Hsurv4) stimulated a significant number of 85 We have extended those previous findings in the current specific IFNgC CD3C T lymphocytes in the donors (Fig. 1). In study, which involves the pre-clinical development of an opti- contrast, overall responses to Hsurv4 peptide did not significantly mized version of FP-surv designed for human immunization differ from controls, which consisted of T cells stimulated with (HIvax). With the purpose of identifying survivin-derived pepti- unpulsed DC (No pep) or irrelevant peptide pulsed DC (Irr 140 des that are highly immunogenic for the most common HLAs in pep). These experiments were reproduced at least in triplicate in 90 the human population, the survivin protein was analyzed using 10 healthy donors, each having a different haplotype, to assess an innovative epitope-prediction algorithm called Epi the efficacy of the peptides in various HLA settings. Data repre- 19-22 Matrix. The immunogenicity of the predicted peptides was senting CD3C T cell responses to survivin peptides for each indi- confirmed in co-culture experiments using autologous DC and T vidual donor are included in Supplemental Table 3. 145 cells isolated from human healthy donors. The sequences encod- 95 ing peptides, confirmed to induce CTLs activation in these co- Selected survivin peptides induce IFNg secretion in human cultures, were then inserted in a transgene optimized for presen- CD4C and CD8C T cells tation of processed peptides on MHC-I (HIvax1). Similarly, We next evaluated separately the activation of CD3C T cell sequences for peptides found to activate Th cells were included subpopulations: CD3C/CD4C T cells and CD3C/CD8C T cells. in a transgene engineered to present antigens on MHC-II Lymphocytes purified from peripheral blood were cultured with 150 100 (HIvax2). One of the predicted MHC-I restricted peptides, (sur- autologous DC loaded with
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