1. Combining STING-based neoantigen-targeted vaccine with checkpoint modulators enhances antitumor immunity in murine pancreatic cancer.
- Author
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Kinkead HL, Hopkins A, Lutz E, Wu AA, Yarchoan M, Cruz K, Woolman S, Vithayathil T, Glickman LH, Ndubaku CO, McWhirter SM, Dubensky TW Jr, Armstrong TD, Jaffee EM, and Zaidi N
- Subjects
- Adenocarcinoma genetics, Adenocarcinoma immunology, Adjuvants, Immunologic administration & dosage, Animals, Antigens, Neoplasm genetics, Antigens, Neoplasm immunology, Antineoplastic Agents, Immunological therapeutic use, Cancer Vaccines genetics, Cancer Vaccines immunology, Cell Line, Tumor transplantation, Combined Modality Therapy methods, Disease Models, Animal, Epitopes, T-Lymphocyte genetics, Epitopes, T-Lymphocyte immunology, Humans, Immunogenicity, Vaccine, Membrane Proteins immunology, Mice, Pancreatic Neoplasms genetics, Pancreatic Neoplasms immunology, Programmed Cell Death 1 Receptor antagonists & inhibitors, Programmed Cell Death 1 Receptor immunology, Receptors, OX40 agonists, Receptors, OX40 immunology, Treatment Outcome, Tumor Escape drug effects, Tumor Escape immunology, Vaccines, Subunit administration & dosage, Vaccines, Subunit genetics, Vaccines, Subunit immunology, Adenocarcinoma therapy, Antineoplastic Agents, Immunological pharmacology, Cancer Vaccines administration & dosage, Immunotherapy methods, Pancreatic Neoplasms therapy
- 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.
- Published
- 2018
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