Abstract
Personalized neoantigen (neoAg) vaccines have shown clinical promise in solid tumors, yet their efficacy and mechanistic basis in hematopoietic malignancies remain poorly defined. Here, we establish an immunocompetent syngeneic A20 B-cell lymphoma platform to test neoAg vaccination as mono- and combinatorial therapy with immune checkpoint therapy (ICT). In a subcutaneous model refractory to single-agent ⍺-PD-1 or ⍺-CTLA4, dual ICT (⍺-PD-1+⍺-CTLA4) eradicated established tumors in a T cell-dependent manner. By mapping antigen specificity of dual-ICT-elicited T cells, we identified dominant endogenous A20 neoantigens and designed therapeutic synthetic long peptide (SLP) vaccines encompassing MHC-I and MHC-II neoepitopes. A20 neoantigen vaccination promoted robust neoAg-specific CD4⁺ and CD8⁺ T cell responses and induced tumor rejection in ~70% of tumor-bearing mice. In contrast, subcutaneous A20 tumor rejection was observed when A20 neoantigen vaccination was combined with PD-1 blockade therapy. To model disseminated disease, we developed a systemic A20 lymphoma protocol in which dual ICT alone failed to control tumor progression. In this setting, A20 neoantigen vaccines delayed disease and prolonged survival, and A20 neoantigen vaccines plus dual ICT achieved durable systemic tumor rejection without overt toxicity. Mechanistically, this latter combination amplified A20 neoAg-specific T cell priming and reshaped their differentiation trajectories, preventing terminal T cell dysfunction while sustaining the cytotoxic capacity of CD8+ T cells and inducing Th1-skewed effector states of CD4+ T cells across tumor and peripheral compartments. Together, these data define a framework for personalized neoAg vaccination in lymphoma and demonstrate that neoAg vaccines can synergize with checkpoint modulation to generate durable systemic anti-tumor immunity.
Committee Chair
Robert Schreiber
Committee Members
Daved Fremont; Erika Crouch; Marco Colonna; Maxim Artyomov; Todd Fehniger
Degree
Doctor of Philosophy (PhD)
Author's Department
Biology & Biomedical Sciences (Biochemistry)
Document Type
Dissertation
Date of Award
4-21-2026
Language
English (en)
DOI
https://doi.org/10.7936/vtmk-tr76
Recommended Citation
Song, Yuang, "Personalized Neoantigen Vaccine-Based Therapies for B-Cell Lymphoma: A Proof-of-Concept Study in Syngeneic Mouse Models of A20 Lymphoma" (2026). Arts & Sciences Graduate Student Theses and Dissertations. 3772.
The definitive version is available at https://doi.org/10.7936/vtmk-tr76