A Combination of Cowpea Mosaic Virus and Immune Checkpoint Therapy Synergistically Improves Therapeutic Efficacy in Three Tumor Models

Abstract Immune checkpoint therapy (ICT) has the potential to treat cancer by removing the immunosuppressive brakes on T cell activity. However, ICT benefits only a subset of patients because most tumors are “cold”, with limited pre‐infiltration of effector T cells, poor immunogenicity, and low‐level expression of checkpoint regulators. It has been previously reported that Cowpea mosaic virus (CPMV) promotes the activation of multiple innate immune cells and the secretion of pro‐inflammatory cytokines to induce T cell cytotoxicity, suggesting that immunostimulatory CPMV could potentiate ICT. Here it is shown that in situ vaccination with CPMV increases the expression of checkpoint regulators on Foxp3⁻CD4⁺ effector T cells in the tumor microenvironment. It is shown that combined treatment with CPMV and selected checkpoint‐targeting antibodies, specifically anti‐PD‐1 antibodies, or agonistic OX40‐specific antibodies, reduced tumor burden, prolonged survival, and induced tumor antigen‐specific immunologic memory to prevent relapse in three immunocompetent syngeneic mouse tumor models. This study therefore reveals new design principles for plant virus nanoparticles as novel immunotherapeutic adjuvants to elicit robust immune responses against cancer.