Tumor-Targeted Nonablative Radiation Promotes Solid Tumor CAR T-cell Therapy Efficacy

Abstract

Infiltration of tumor by T cells is a prerequisite for successful immunotherapy of solid tumors. In this study, we investigate the influence of tumor-targeted radiation on chimeric antigen receptor (CAR) T-cell therapy tumor infiltration, accumulation, and efficacy in clinically relevant models of pleural mesothelioma and non-small cell lung cancers. We use a non-ablative dose of tumor-targeted radiation prior to systemic administration of mesothelin-targeted CAR T cells to assess infiltration, proliferation, anti-tumor efficacy, and functional persistence of CAR T cells at primary and distant sites of tumor. A tumor-targeted, non-ablative dose of radiation promotes early and high infiltration, proliferation, and functional persistence of CAR T cells. Tumor-targeted radiation promotes tumor-chemokine expression and chemokine-receptor expression in infiltrating T cells, and results in a subpopulation of higher-intensity CAR-expressing T cells with high co-expression of chemokine receptors that further infiltrate distant sites of disease, enhancing CAR T-cell anti-tumor efficacy. Enhanced CAR T-cell efficacy is evident in models of both high-mesothelin-expressing mesothelioma and mixed-mesothelin-expressing lung cancer—two thoracic cancers for which radiation therapy is part of the standard of care. Our results strongly suggest that the use of tumor-targeted radiation prior to systemic administration of CAR T cells may substantially improve CAR T-cell therapy efficacy for solid tumors. Building on our observations, we describe a translational strategy of “sandwich” cell therapy for solid tumors that combines sequential metastatic site–targeted radiation and CAR T cells—a regional solution to overcome barriers to systemic delivery of CAR T cells.

Low-dose targeted radionuclide therapy synergizes with CAR T cells and enhances tumor response

“…Low-dose external radiation has demonstrated to sensitize tumor cells to T cell cytolytic activity through mechanisms involving tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and Fas ligand (FasL) ( 7 , 8 , 50 ). Moreover, nonablavtive external radiation can induce tumor secretion of chemokines and promote the upregulation of chemokine receptors in tumor-infiltrating CAR T cells and a central memory phenotype ( 51 ). However, the biological and immunomodulatory effects of radiation can differ significantly between external radiation generated within minutes and internal radiation persisting for days to weeks.…”

Proton radiation boosts the efficacy of mesothelin-targeting chimeric antigen receptor T cell therapy in pancreatic cancer

“…They found an increased accumulation of CAR T cells in the tumor, attributed to a dose-dependent increase in the expression of several chemokines and chemokine receptors in the infiltrating T cells. Nonetheless, exposure to 4 Gy photon RT did not enhance MSLN expression in cancer cells when tested in vitro ( 45 ). Considering these findings collectively, it is possible that proton RT enhances the sensitivity of PDAC tumors to MSLN-targeting CAR T therapy by elevating the presence of the target protein on the cancer cell surface.…”

DLL3-targeted CAR T-cell therapy in pre-clinical models for small cell lung cancer: safety, efficacy, and challenges

“…Although subcutaneous models are useful for proof-of-principle studies, the limitation of subcutaneous models is that the models do not faithfully mimic clinical disease. In contrast, results from clinically relevant models harboring disease at multiple sites could be more relevant, especially in terms of CAR T-cell efficacy in solid tumor models ( 15 , 16 ). The authors investigated the efficacy of DLL3-targeted CAR T cells in a systemic tumor model established by SCLC cell lines treated via tail vein to mimic a metastatic-stage disease commonly seen in the clinical setting.…”