Maine et al. designed self-replicating RNA vaccines engineered to evade protein translation shutdown and encode multiple predicted tumor neoepitopes with or without cytokines. Vaccination of mice induced epitope-specific polyfunctional CD4+ and CD8+ T cell responses that were differentially impacted by the design of poly-epitopes and the prime/boost interval, and were enhanced by cytokines, which promoted epitope spreading. Therapeutic vaccination of a mouse tumor model induced specific antitumor activity associated with antigen responses and was enhanced by anti-PD-1. Immunization of rhesus macaques induced polyfunctional CD4+ and CD8+ T cell responses.
Contributed by Paula Hochman
ABSTRACT: Historically poor clinical results of tumor vaccines have been attributed to weakly immunogenic antigen targets, limited specificity, and vaccine platforms that fail to induce high-quality polyfunctional T cells, central to mediating cellular immunity. We show here that the combination of antigen selection, construct design, and a robust vaccine platform based on the Synthetically Modified Alpha Replicon RNA Technology (SMARRT), a self-replicating RNA, leads to control of tumor growth in mice. Therapeutic immunization with SMARRT replicon-based vaccines expressing tumor-specific neoantigens or tumor-associated antigen were able to generate polyfunctional CD4(+) and CD8(+) T cell responses in mice. Additionally, checkpoint inhibitors, or co-administration of cytokine also expressed from the SMARRT platform, synergized to enhance responses further. Lastly, SMARRT-based immunization of non-human primates was able to elicit high quality T cell responses, demonstrating translatability and clinical feasibility of synthetic replicon technology for therapeutic oncology vaccines.
Author Info: (1) Synthetic Genomics, Inc., La Jolla, California, United States. Electronic address: cmaine@its.jnj.com. (2) EpiVax Therapeutics, Inc., New York, New York, United States. (3) Syn
Author Info: (1) Synthetic Genomics, Inc., La Jolla, California, United States. Electronic address: cmaine@its.jnj.com. (2) EpiVax Therapeutics, Inc., New York, New York, United States. (3) Synthetic Genomics, Inc., La Jolla, California, United States. (4) Synthetic Genomics, Inc., La Jolla, California, United States. (5) Synthetic Genomics, Inc., La Jolla, California, United States. (6) EpiVax, Inc., Providence, Rhode Island, United States; University of Rhode Island, Providence, Rhode Island, United States; University of Georgia, Athens, Georgia, United States. (7) Synthetic Genomics, Inc., La Jolla, California, United States. (8) Synthetic Genomics, Inc., La Jolla, California, United States. (9) Synthetic Genomics, Inc., La Jolla, California, United States. (10) Synthetic Genomics, Inc., La Jolla, California, United States. (11) Synthetic Genomics, Inc., La Jolla, California, United States. (12) Synthetic Genomics, Inc., La Jolla, California, United States. (13) Synthetic Genomics, Inc., La Jolla, California, United States. (14) Synthetic Genomics, Inc., La Jolla, California, United States. (15) Synthetic Genomics, Inc., La Jolla, California, United States. (16) Synthetic Genomics, Inc., La Jolla, California, United States. (17) Synthetic Genomics, Inc., La Jolla, California, United States. (18) EpiVax Therapeutics, Inc., New York, New York, United States. (19) EpiVax, Inc., Providence, Rhode Island, United States; University of Georgia, Athens, Georgia, United States. (20) Synthetic Genomics, Inc., La Jolla, California, United States. (21) Synthetic Genomics, Inc., La Jolla, California, United States.
