肿瘤细胞被T细胞浸润是固态肿瘤成功免疫疗法的前提。在本研究中，我们调查了肿瘤靶向放射治疗对嵌合抗原受体（CAR）T细胞疗法肿瘤浸润、积累和疗效的影响，采用临床相关模型（胸腔间皮瘤和非小细胞肺癌）。我们在系统给予基于纤维蛋白素的CAR T细胞之前使用非消融剂量的肿瘤靶向放射治疗，以评估T细胞在肿瘤原发和远隔部位的浸润、增殖、抗肿瘤疗效和功能持久性。靶向肿瘤的非消融剂量放射治疗促进了CAR T细胞的早期高浸润、增殖和功能持久性。靶向肿瘤的放射治疗促进了浸润的T细胞中肿瘤趋化因子和趋化因子受体的表达，并导致高表达趋化因子受体的高强度CAR T细胞的亚群浸润到疾病的远隔部位，增强了CAR T细胞的抗肿瘤疗效。增强的CAR T细胞疗效在表达高水平纤维蛋白素的胸腔间皮瘤和混合表达纤维蛋白素的肺癌模型中均得到了证实，而这两种恶性肿瘤通常都使用放射治疗作为标准治疗手段。我们的结果强烈暗示，靶向肿瘤的放射治疗可能会大幅提高固态肿瘤CAR T细胞疗法的疗效。根据我们的观察，我们提出了一种“三明治”细胞疗法的转化策略，该策略将转移部位靶向放射治疗与CAR T细胞结合，从而解决困扰CAR T细胞系统输送的障碍，实现区域治疗方案。

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.