癌症研究
间皮素
医学
免疫疗法
放射治疗
嵌合抗原受体
靶向治疗
间皮瘤
趋化因子
病理
免疫学
癌症
免疫系统
内科学
作者
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 R. de Biasi,Masha Zeltsman,Marissa Mayor,Aurore Morello,Vivek Mittal,Daniel R. Gomez,Andreas Rimner,David R. Jones,Prasad S. Adusumilli
出处
期刊:Cancer immunology research
[American Association for Cancer Research]
日期:2023-08-04
卷期号:11 (10): 1314-1331
被引量:1
标识
DOI:10.1158/2326-6066.cir-22-0840
摘要
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.
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