title: Optimization of Peptide Vaccines to Induce Robust Antitumor CD4 T-cell Responses.
abstract: Substantial evidence indicates that immunotherapy is a feasible and effective approach for the treatment of numerous types of cancer. Among various immunotherapy options, peptide vaccines to generate antitumor T cells appear as promising candidates, because of their cost effectiveness and ease of implementation. Nevertheless, most peptide vaccines are notorious for being weekly immunogenic and, thus, optimization of the vaccination strategy is essential to achieve therapeutic effectiveness. In addition, effective peptide vaccines must stimulate both CD8 cytotoxic and CD4 helper T lymphocytes. Our group has been successful in designing effective peptide vaccination strategies for inducing CD8 T-cell responses in mouse tumor models. Here, we describe a somewhat similar, but distinct, peptide vaccination strategy capable of generating vast CD4 T-cell responses by combining synthetic peptides with toll-like receptor (TLR) agonists and OX40/CD40 costimulation. This vaccination strategy was efficient in overcoming immune tolerance to a self-tumor-associated antigen and generated significant antitumor effects in a mouse model of malignant melanoma. The optimized peptide vaccine also allowed the expansion of adoptively transferred CD4 T cells without the need for lymphodepletion and IL2 administration, generating effective antimelanoma responses through the enhancement of proliferative and antiapoptotic activities of CD4 T cells. These results have practical implications in the design of more effective T-cell-based immunotherapies. Cancer Immunol Res; 5(1); 72-83. ©2016 AACR.
authors.affiliation: Cancer Immunology, Inflammation and Tolerance Program, Augusta University, Georgia Cancer Center, Augusta, Georgia.|Department of Innovative Research for Diagnosis and Treatment of Head & Neck Cancer, Asahikawa Medical University, Asahikawa, Japan.|Department of Pathology, Asahikawa Medical University, Asahikawa, Japan.|Department of Otolaryngology, Head and Neck Surgery, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Takumi
authors.initials: T
authors.lastname: Kumai
authors.affiliation: Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia.|Children's Healthcare of Atlanta, Atlanta, Georgia.
authors.forename: Sujin
authors.initials: S
authors.lastname: Lee
authors.affiliation: Catholic Hematopoietic Stem Cell Bank, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Hyun-Il
authors.initials: HI
authors.lastname: Cho
authors.affiliation: Cancer Immunology, Inflammation and Tolerance Program, Augusta University, Georgia Cancer Center, Augusta, Georgia.
authors.forename: Hussein
authors.initials: H
authors.lastname: Sultan
authors.affiliation: Department of Pathology, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Hiroya
authors.initials: H
authors.lastname: Kobayashi
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Harabuchi
authors.affiliation: Cancer Immunology, Inflammation and Tolerance Program, Augusta University, Georgia Cancer Center, Augusta, Georgia. ecelis@augusta.edu.
authors.forename: Esteban
authors.initials: E
authors.lastname: Celis
mesh_terms: D000276:Adjuvants, Immunologic; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D007108:Immune Tolerance / Q000187:drug effects; D007167:Immunotherapy; D016219:Immunotherapy, Adoptive; D007372:Interferons / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D053262:Receptors, OX40 / Q000819:agonists; D051193:Toll-Like Receptors / Q000378:metabolism; D022223:Vaccines, Subunit / Q000008:administration & dosage / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D053262:Receptors, OX40; D051193:Toll-Like Receptors; D022223:Vaccines, Subunit; D007372:Interferons