Abstract LB382: synDNA vaccines against TCR and EL4 derived neoantigens induce tumor control in a murine T cell lymphoma model

Abstract T cell lymphomas constitute approximately 10% of all non-Hodgkin lymphomas and are associated with poor prognosis. Patients experiencing early relapse exhibit a 5-year overall survival rate of only 11%, underscoring the urgent need for novel therapeutic strategies. T cell cancers are predominantly clonal, making the T cell receptor (TCR) an appealing target for immunotherapy. Additionally, neoantigens, derived from somatic mutations within tumor cells, present another promising target for anti-cancer vaccine development. In this study, we developed and evaluated two synDNA vaccines: one targeting the TCR⍺, β, and γ chains (TCRfull), and another targeting 15 neoantigens identified through whole exome sequencing and RNA sequencing of the EL4 murine T cell lymphoma model (EL4neo). Immunogenicity studies revealed robust immune responses against all three TCR chains, with identification of immunodominant peptides for each chain. Notably, no significant differences in the number of live T cells were observed between TCRfull-vaccinated mice and control groups, indicating the vaccine's ability to selectively break tolerance against the vaccinated TCR without broadly depleting T cells. The EL4neo vaccine elicited strong immune responses against 5/15 encoded neoantigens. In a minimal residual disease model, both vaccines independently delayed EL4 tumor progression and improved survival of tumor bearing mice. Analysis of tumors from TCRfull treated mice revealed downregulation of TCR expression. This suggests that under immune pressure, tumors can downregulate TCR expression highlighting a potential immune escape mechanism. Co-administration of the TCRfull and EL4neo vaccines achieved superior tumor control compared to either vaccine alone, and further improved animal survival, demonstrating that neoantigen targeting can partially mitigate TCR antigen loss. These findings highlight the potential of combining TCR-targeted and neoantigen-based immunotherapies for the treatment of T cell lymphomas. Further investigation of this dual-vaccine approach is warranted to optimize its therapeutic efficacy and provide a novel therapeutic approach for this difficult to treat cancer. Citation Format: Pratik Sanjivkumar Bhojnagarwala, Joshua Jose, David B. Weiner. synDNA vaccines against TCR and EL4 derived neoantigens induce tumor control in a murine T cell lymphoma model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB382.