journal contribution
posted on 2023-10-04, 07:20 authored by Hue Tu Quach, Matthew S. Skovgard, Jonathan Villena-Vargas, Rebecca Y. Bellis, Navin K. Chintala, Alfredo Amador-Molina, Yang Bai, Srijita Banerjee, Jasmeen Saini, Yuquan Xiong, William-Ray Vista, Alexander J. Byun, Andreas De Biasi, Masha Zeltsman, Marissa Mayor, Aurore Morello, Vivek Mittal, Daniel R. Gomez, Andreas Rimner, David R. Jones, Prasad S. Adusumilli Supplementary Figures 1-13 with associated legends
Funding
National Institutes of Health (NIH)
U.S. Department of Defense (DOD)
Commonwealth Foundation for Cancer Research Foundation
Derfner Foundation (The Derfner Foundation)
Atara Biotherapeutics (Atara)
Dalle Pezze Foundation
Esophageal Cancer Education Fund
Miner Fund for Mesothelioma Research
History
ARTICLE 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 nonablative dose of tumor-targeted radiation prior to systemic administration of mesothelin-targeted CAR T cells to assess infiltration, proliferation, antitumor efficacy, and functional persistence of CAR T cells at primary and distant sites of tumor. A tumor-targeted, nonablative 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 coexpression of chemokine receptors that further infiltrate distant sites of disease, enhancing CAR T-cell antitumor 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 radiotherapy 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.
