CD4 T cell–activating neoantigens enhance personalized cancer vaccine efficacy

Personalized cancer vaccines aim to activate and expand cytotoxic antitumor CD8⁺ T cells to recognize and kill tumor cells. However, the role of CD4⁺ T cell activation in the clinical benefit of these vaccines is not well defined. We previously established a personalized neoantigen vaccine (PancVAX) for the pancreatic cancer cell line Panc02, which activates tumor-specific CD8⁺ T cells but required combinatorial checkpoint modulators to achieve therapeutic efficacy. To determine the effects of neoantigen-specific CD4⁺ T cell activation, we generated a vaccine (PancVAX2) targeting both major histocompatibility complex class I– (MHCI-) and MHCII-specific neoantigens. Tumor-bearing mice vaccinated with PancVAX2 had significantly improved control of tumor growth and long-term survival benefit without concurrent administration of checkpoint inhibitors. PancVAX2 significantly enhanced priming and recruitment of neoantigen-specific CD8⁺ T cells into the tumor with lower PD-1 expression after reactivation compared with the CD8⁺ vaccine alone. Vaccine-induced neoantigen-specific Th1 CD4⁺ T cells in the tumor were associated with decreased Tregs. Consistent with this, PancVAX2 was associated with more proimmune myeloid-derived suppressor cells and M1-like macrophages in the tumor, demonstrating a less immunosuppressive tumor microenvironment. This study demonstrates the biological importance of prioritizing and including CD4⁺ T cell–specific neoantigens for personalized cancer vaccine modalities.