Self-Replicating RNAs Drive Protective Anti-tumor T Cell Responses to Neoantigen Vaccine Targets in a Combinatorial Approach.

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.

• Authors: Christian J Maine, Guilhem Richard, Darina S Spasova, Shigeki J Miyake-Stoner, Jessica Sparks, Leonard Moise, Ryan P Sullivan, Olivia Garijo, Melissa Choz, Jenna M Crouse, Allison Aguilar, Melanie D Olesiuk, Katie Lyons, Katrina Salvador, Melissa Blomgren, Jason L DeHart, Kurt I Kamrud, Gad Berdugo, Anne S De Groot, Nathaniel S Wang, Parinaz Aliahmad
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 29 Issue 3 Pg. 1186-1198 (03 03 2021) ISSN: 1525-0024 [Electronic] United States
• PMID: 33278563 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Chemical References

• Antigens, Neoplasm
• Cancer Vaccines

Topics

• Animals
• Antigens, Neoplasm (immunology)
• CD4-Positive T-Lymphocytes (immunology)
• Cancer Vaccines (administration & dosage, immunology)
• Colonic Neoplasms (genetics, immunology, therapy)
• Female
• Humans
• Immunity, Cellular (immunology)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Primates
• Replicon
• Tumor Cells, Cultured
• Vaccination