低剂量放射性药物治疗增强 B7-H3 靶向 CAR-T 细胞对小鼠转移性神经母细胞瘤的疗效
Low-dose radiopharmaceutical therapy enhances the efficacy of B7-H3 CAR T cells in murine metastatic neuroblastoma
嵌合抗原受体T细胞（CAR-T，改造患者T细胞以攻击肿瘤）在血液肿瘤中有效，但对实体瘤效果有限。研究者在培养皿和小鼠转移性神经母细胞瘤模型中，先用放射性药物 177Lu-NM600 给予低剂量照射，再静脉输注靶向 B7-H3 的 CAR-T 细胞。结果显示联合治疗显著延长小鼠总生存期，照射后的肿瘤细胞也更易被 CAR-T 杀死，但 T 细胞耗竭标志物增多，提示可能还需联合免疫检查点抑制剂。作者称这是首次在转移性实体瘤中把基于剂量学的放射性药物治疗与 CAR-T 联合，尚未经同行评审。
为什么推荐给您：首次报告剂量学放射治疗联合CAR-T用于转移性实体瘤，动物水平阳性，具转化前景。
不需要生物学背景，多打比方
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摘要Abstract
Background: Chimeric antigen receptor (CAR) T cell therapy has had clinical success in hematologic malignancies, but limited efficacy is seen in solid tumors. In this study, we investigated whether systemic CAR T cell therapy could be enhanced in metastatic models of neuroblastoma when combined with radiopharmaceutical therapy (RPT). Methods: Non-irradiated or irradiated tumor cells were co-cultured with CAR T cells (1:1) in vitro and supernatant media was subsequently collected for cytokines analyses. CAR T cell phenotypes were characterized by flow cytometry including checkpoint marker expression. Xenograft models of metastatic neuroblastoma were generated in NOD-Rag1nullIL2rgnull (NRG) mice. Tumor-bearing mice received 1.8 Gy of radiation delivered by 177Lu-NM600 RPT five days after tumor implantation. Nine days after RPT, CAR T cells were administered intravenously. To evaluate tumor burden, mice were imaged weekly for 4 weeks. Results: In models of metastatic neuroblastoma, 177Lu-NM600 RPT significantly increased overall survival when combined with CAR T cell therapy in vivo. Pre-treatment of tumor cells with 177Lu also significantly increased CAR T cell cytotoxicity while decreasing production of IL-4 and IL-10 in vitro. Co-culture of CAR T cells with irradiated tumors led to increases in PD-1+TIM3+LAG3+ T cells, suggesting that further combination with immune checkpoint inhibitors may enhance clinical efficacy. Conclusions: Our findings demonstrate that low-dose RPT can potentiate the anti-tumor efficacy of CAR T cells in metastatic neuroblastoma. To our knowledge, this is the first report of dosimetry-based RPT being combined with CAR T cells in a metastatic solid tumor setting. These findings underscore the potential of combining RPT and CAR T cells to overcome the unique challenges of solid tumors, particularly when treating metastatic disease.