Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, New York.
Cancer Immunol Res. 2023 Oct 4;11(10):1314-1331. doi: 10.1158/2326-6066.CIR-22-0840.
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.
T 细胞浸润是实体瘤成功免疫治疗的前提。在这项研究中，我们研究了肿瘤靶向放疗对嵌合抗原受体（CAR）T 细胞治疗肿瘤浸润、积累和疗效的影响，这些研究建立在胸膜间皮瘤和非小细胞肺癌的临床相关模型上。我们在全身给予间皮素靶向 CAR T 细胞之前使用肿瘤靶向的非消融剂量的辐射，以评估 CAR T 细胞在原发性和肿瘤远处部位的浸润、增殖、抗肿瘤疗效和功能持久性。肿瘤靶向的非消融剂量的辐射促进了 CAR T 细胞的早期和高浸润、增殖和功能持久性。肿瘤靶向放疗促进了肿瘤趋化因子的表达和浸润 T 细胞中趋化因子受体的表达，并导致具有高趋化因子受体共表达的高表达 CAR 的 T 细胞亚群进一步浸润疾病的远处部位，从而增强了 CAR T 细胞的抗肿瘤疗效。在高表达间皮素的间皮瘤和混合表达间皮素的肺癌这两种胸癌模型中都观察到了增强的 CAR T 细胞疗效，这两种癌症的放射治疗都是标准治疗的一部分。我们的研究结果强烈表明，在全身给予 CAR T 细胞之前使用肿瘤靶向放疗可能会显著提高实体瘤的 CAR T 细胞治疗疗效。在此基础上，我们描述了一种用于实体瘤的“三明治”细胞治疗的转化策略，该策略结合了序贯转移部位靶向放疗和 CAR T 细胞，这是一种克服 CAR T 细胞全身递送障碍的局部解决方案。
