Personalized Neoantigen Vaccines Synergize with Immune Checkpoint Therapy and CD8-Targeted Cytokines to Control B-Cell Lymphoma

A personalized neoantigen vaccine has proven effective when combined with immune checkpoint therapy and CD8-targeted cytokines, specifically in the treatment of B-cell lymphoma. Initially, subcutaneous A20 tumors were resistant to single-agent anti-PD-1 or anti-CTLA4 therapy; however, dual immune checkpoint therapy yielded a 90% eradication rate in T cell-dependent manner. By identifying dominant endogenous A20 MHC-I and MHC-II neoantigens, researchers created a therapeutic synthetic long peptide (SLP) vaccine.

This A20 neoVAX vaccine stimulated robust neoantigen-specific CD4 and CD8 T cell responses in mice, leading to tumor rejection in approximately 70% of cases. When tested in an immunocompetent syngeneic A20 B-cell lymphoma platform, dual immune checkpoint therapy was initially ineffective. However, A20 neoVAX combined with anti-PD-1 delayed tumor progression and prolonged animal survival. The combination of A20 neoVAX plus dual immune checkpoint therapy achieved durable systemic tumor elimination.

To minimize potential adverse events, genetically modified CD8-targeted cytokine muteins (CD8-IL2 or CD8-IL21) were used in place of anti-CTLA4. When A20 neoVAX was combined with CD8-IL2 or CD8-IL21 and anti-PD-1, 66.7% of tumor-bearing mice successfully rejected their lymphoma. Similarly, when CD8-IL21 replaced CD8-IL2, tumor clearance was observed in two-thirds of A20-bearing mice, without the need for anti-PD-1.

These findings provide a framework for optimal personalized neoantigen vaccination in B-lymphoma, demonstrating that neoantigen vaccines can safely synergize with CD8+ T cell-selective immunotherapies to prevent T-cell dysfunction and generate durable systemic anti-tumor immunity.