Abstract B121: Personalized neoantigen vaccine-based therapies in syngeneic mouse models of lymphoma: Development of neoantigen-specific immunotherapies for mouse A20 lymphoma

Abstract Neoantigen vaccines represent a promising immunotherapeutic approach against cancer. Ongoing work from our lab and others has facilitated neoantigen discovery and neoantigen-specific immunotherapy design that can lead to the elimination of established tumors without inducing toxicity. While early personalized neoantigen vaccine therapies for tumor-bearing mice and human cancer patients have produced encouraging results, neoantigen vaccines have not been fully investigated in either mouse or human B-cell lymphoma. Here, to investigate the potential therapeutic benefits of lymphoma neoantigen vaccines, we employed a syngeneic BALB/c mouse lymphoma model using the transplantable B cell lymphoma A20. Whereas immune checkpoint monotherapy (ICT) with ⍺CTLA-4, ⍺PD-1, or ⍺PD-L1 failed to eliminate established A20 tumors, the combination of ⍺CTLA-4 plus ⍺PD-1 induced complete A20 tumor rejection. Rejection was dependent on CD4+ and CD8+ T cells. To characterize the antigen specificity of lymphocytes that were required for combination ICT-dependent A20 tumor rejection, we identified the MHC-I and MHC-II neoantigens expressed in A20 cells (S295F-LRRK1 (H2-Ld), R325I-AARS (I-Ed), and A25V-PRKCB(I-Ed)) and mapped the time course of the T cell response following treatment with the combination of ⍺CTLA-4 + ⍺PD-1. To test the immunogenicity of our A20-specific neoantigen vaccine, we treated naïve BALB/c mice with a synthetic long peptide vaccine (SLP) containing the A20 MHC-I + MHC-II neoantigens plus poly-ICLC and detected predominant MHC-I and MHC-II neoantigen-specific T cell responses by ELISPOT analyses that were not observed in mice vaccinated with the corresponding wild type sequences. Treatment of A20 tumor-bearing mice with the A20-specific neoantigen vaccine plus adjuvant drove efficient rejection of A20 lymphomas but only when the vaccines contained both MHC-I and MHC-II neoantigens. The A20 neoantigen vaccine also significantly enhanced neoantigen-specific T-cell infiltration into the tumors and induced epitope spreading to other A20 antigens that had not been included in the vaccine. To investigate the optimal neoantigen vaccine condition, we also revealed the importance of MHC-II neoantigen concentration in the vaccine by showing that the lower dosage of A20 MHC-II neoantigen combined with MHC-I neoantigen achieved better efficacy compared to the higher dosage of A20 MHC-II neoantigen combinations. In the end, we found ICT ⍺PD-1 can further improve the antitumor efficacy of the A20 neoantigen vaccine and fully eliminate established A20 tumors. These data provide proof of concept that we can successfully identify lymphoma neoantigens and design neoantigen-specific immunotherapies that are efficacious in treating progressive lymphoma. Citation Format: Yuang Song, Hussein Sultan, Cora D. Arthur, J Michael White, Heather Kohlmiller, Kathleen C.F. Sheehan, Maxim N. Artyomov, Obi L. Griffith, Malachi Griffith, Robert D. Schreiber. Personalized neoantigen vaccine-based therapies in syngeneic mouse models of lymphoma: Development of neoantigen-specific immunotherapies for mouse A20 lymphoma [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B121.