Irreversible Electroporation Enhances Solid Tumor Infiltration and Selective Cancer Cell Lysis by CAR T Cells

Abstract Purpose: One recurring challenge in cell therapy for solid tumors is poor tumor infiltration of adoptively transferred T cells. We previously showed that a subablative dose of tumor-targeted radiation generates a chemokine gradient that promotes infiltration, proliferation, and a memory phenotype of chimeric antigen receptor (CAR) T cells in solid tumors. However, radiation is cytotoxic to infiltrating CAR T cells, limiting its repeated use. Experimental Design: We hypothesized that irreversible electroporation could generate a chemokine gradient that promotes CAR T-cell infiltration into solid tumors and that selective irreversible electroporation (sIRE) tuned for selective cancer cell lysis (thus, sparing infiltrating CAR T cells) can be used in a repeated fashion. Using experimental screening and simulation models, we optimized sIRE parameters to kill cancer cells while sparing T cells. Results: Using 3D tumor mimics and mouse models of malignant pleural mesothelioma, we confirmed the therapeutic benefit of repeated sIRE. Chemokine secretion by cancer cells injured by sIRE promoted migration and tumor infiltration of systemically administered CAR T cells and facilitated sustained immunity in a tumor-rechallenge model. Conclusions: By leveraging a dual-purpose translational strategy—through direct cancer cell–targeted cytotoxicity and augmented CAR T-cell infiltration—sIRE can reduce cancer burden while preserving and enhancing CAR T-cell function.