靶向 CD19 的嵌合抗原受体 (CAR) T 细胞疗法 (CART-19) 代表了治疗复发或难治性 CD19 阳性 B 细胞淋巴瘤患者的重大进展。然而，很大一部分患者要么复发，要么没有反应。此外，许多患者有症状，需要在CAR-T细胞制造期间进行桥接放射治疗（RT）。为了研究 1-2 次低剂量 RT 对 CART-19 治疗反应的影响，我们开发了一种使用 A20 淋巴瘤细胞进行 CART-19 治疗的小鼠模型。我们发现低剂量分割放疗对于在照射部位以外产生远隔全身抗肿瘤反应具有积极作用。 RT 与 CART-19 疗法的结合对受辐射肿块中的肿瘤生长产生了附加效应。值得注意的是，在未照射的肿瘤中观察到抗肿瘤效果显着增加。从机制上讲，我们的结果验证了 cGAS/STING 通路的激活、肿瘤相关抗原 (TAA) 交叉引发以及表位扩散的引发。总的来说，我们的研究结果表明，RT 可能作为 CAR-T 细胞治疗的最佳启动和桥接方式，克服 CD19 阳性血液恶性肿瘤患者的治疗耐药性并改善临床结果。版权所有 © 2024 美国血液学会。

Chimeric antigen receptor (CAR) T cell therapy targeting CD19 (CART-19) represents a significant advance in the treatment of patients with relapsed or refractory CD19-positive B-cell lymphomas. However, a significant portion of patients either relapse or fail to respond. Moreover, many patients have symptomatic disease, requiring bridging radiation therapy (RT) during the period of CAR-T cells manufacturing. To investigate the impact of 1-2 fractions of low-dose RT on CART-19 treatment response, we developed a mouse model using A20 lymphoma cells for CART-19 therapy. We found that low dose fractionated RT had a positive effect on generating abscopal systemic antitumor responses beyond the irradiated site. The combination of RT with CART-19 therapy resulted in additive effects on tumor growth in irradiated masses. Notably, a significant additional increase in antitumor effect was observed in non-irradiated tumors. Mechanistically, our results validate activation of the cGAS/STING pathway, tumor-associated antigen (TAA) cross-priming, and elicitation of epitope spreading. Collectively, our findings suggest that RT may serve as an optimal priming and bridging modality for CAR-T cell therapy overcoming treatment resistance and improving clinical outcomes in patients with CD19-positive hematologic malignancies.Copyright © 2024 American Society of Hematology.