Abstract
Tumor neoantigens arising from somatic mutations in the cancer genome are less likely to be subject to central immune tolerance and are therefore attractive targets for vaccine immunotherapy. We utilized whole-exome sequencing, RNA sequencing (RNASeq), and an in silico immunogenicity prediction algorithm, NetMHC, to generate a neoantigen-targeted vaccine, PancVAX, which was administered together with the STING adjuvant ADU-V16 to mice bearing pancreatic adenocarcinoma (Panc02) cells. PancVAX activated a neoepitope-specific T cell repertoire within the tumor and caused transient tumor regression. When given in combination with two checkpoint modulators, namely anti-PD-1 and agonist OX40 antibodies, PancVAX resulted in enhanced and more durable tumor regression and a survival benefit. The addition of OX40 to vaccine reduced the coexpression of T cell exhaustion markers, Lag3 and PD-1, and resulted in rejection of tumors upon contralateral rechallenge, suggesting the induction of T cell memory. Together, these data provide the framework for testing personalized neoantigen-based combinatorial vaccine strategies in patients with pancreatic and other nonimmunogenic cancers.
Keywords:
Cancer immunotherapy; Oncology.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / genetics
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Adenocarcinoma / immunology
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Adenocarcinoma / therapy*
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Adjuvants, Immunologic / administration & dosage
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Animals
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Antigens, Neoplasm / genetics
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Antigens, Neoplasm / immunology
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Antineoplastic Agents, Immunological / pharmacology*
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Antineoplastic Agents, Immunological / therapeutic use
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Cancer Vaccines / administration & dosage*
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Cancer Vaccines / genetics
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Cancer Vaccines / immunology
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Cell Line, Tumor / transplantation
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Combined Modality Therapy / methods
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Disease Models, Animal
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Epitopes, T-Lymphocyte / genetics
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Epitopes, T-Lymphocyte / immunology
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Humans
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Immunogenicity, Vaccine
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Immunotherapy / methods*
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Membrane Proteins / immunology
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Mice
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Pancreatic Neoplasms / genetics
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Pancreatic Neoplasms / immunology
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Pancreatic Neoplasms / therapy*
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Programmed Cell Death 1 Receptor / antagonists & inhibitors
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Programmed Cell Death 1 Receptor / immunology
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Receptors, OX40 / agonists
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Receptors, OX40 / immunology
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Treatment Outcome
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Tumor Escape / drug effects
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Tumor Escape / immunology
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Vaccines, Subunit / administration & dosage
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Vaccines, Subunit / genetics
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Vaccines, Subunit / immunology
Substances
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Adjuvants, Immunologic
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Antigens, Neoplasm
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Antineoplastic Agents, Immunological
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Cancer Vaccines
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Epitopes, T-Lymphocyte
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Membrane Proteins
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Pdcd1 protein, mouse
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Programmed Cell Death 1 Receptor
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Receptors, OX40
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STING1 protein, human
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Tnfrsf4 protein, mouse
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Vaccines, Subunit