Tumor Ablation by Irreversible Electroporation Augments PD-1 Checkpoint Inhibitor Immunotherapy in Colon Adenocarcinoma

Abstract

INTRODUCTION: Programmed Cell Death Protein 1 (PD-1) checkpoint inhibitors have recently been approved for microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer (CRC). Response rates are promising in MSI-H-dMMR CRC but remain dismal for microsatellite-stable (MSS) or mismatch repair proficient (pMMR) CRC. >80% of CRCs are MSS-pMMR. Increasing tumor-infiltrating lymphocytes (TILs) may improve checkpoint inhibitor efficacy in CRC. New data suggest irreversible electroporation (IRE) therapy whereby electric pulses cause tumor necrosis and apoptosis; increase tumor-associated protein uptake by dendritic cells, subsequently boosting neoantigen presentation and TILs. We hypothesized that IRE combined with anti–PD-1 antibody, when compared with IRE or anti–PD-1 antibody alone, would increase survival, cause tumor regression by increasing TILs, and guard against secondary tumor challenge by increasing tumor antigen-specific CD8 T cells. METHODS: Using the MC38 cell line derived from murine colon adenocarcinoma, immunohistochemistry, and anti-CD8 antibodies, we evaluated antitumor immune responses in mice. RESULTS: IRE with anti–PD-1 antibody showed statistically significant survival, tumor regression, and increased TILs compared with IRE or anti–PD-1 antibody alone. Seventeen of 18 mice treated with IRE and anti–PD-1 antibody rejected a secondary tumor challenge. Conversely, IRE with anti–PD-1 antibody failed to protect against tumor rechallenge in mice that underwent CD8 T-cell depletion. Zero of 10 CD8 T-cell–depleted mice survived after secondary tumor challenge (Figure).FigureCONCLUSION: These data suggest IRE and anti–PD-1 antibody work in concert to bolster tumor-specific CD8 T-cell immune responses, serving as a pragmatic strategy for overcoming clinical challenges in checkpoint inhibitor immunotherapy for CRC.