Background and purpose. Chimeric antigen receptor (CAR) T cells have been relatively ineffective against solid tumors. Low-dose radiation which can be delivered to multiple sites of metastases by targeted radionuclide therapy (TRT) can elicit immunostimulatory effects. However, TRT has never been combined with CAR T cells against solid tumors in a clinical setting. This study investigated the effects of radiation delivered by Lutetium-177 (177Lu) and Actinium-225 (225Ac) on the viability and effector function of CAR T cells in vitro to evaluate the feasibility of such therapeutic combinations. After the irradiation of anti-GD2 CAR T cells with various doses of radiation delivered by177Lu or225Ac, their viability and cytotoxic activity against GD2-expressing human CHLA-20 neuroblastoma and melanoma M21 cells were determined by flow cytometry. The expression of the exhaustion marker PD-1, activation marker CD69 and the activating receptor NKG2D was measured on the irradiated anti-GD2 CAR T cells. Both177Lu and225Ac displayed a dose-dependent toxicity on anti-GD2 CAR T cells. However, radiation enhanced the cytotoxic activity of these CAR T cells against CHLA-20 and M21 irrespective of the dose tested and the type of radionuclide. No significant changes in the expression of PD-1, CD69 and NKG2D was noted on the CAR T cells following irradiation. Given a lower CAR T cell viability at equal doses and an enhancement of cytotoxic activity irrespective of the radionuclide type,177Lu-based TRT may be preferred over225Ac-based TRT when evaluating a potential synergism between these therapies in vivo against solid tumors.
背景与目的：嵌合抗原受体（CAR）T细胞对实体瘤的疗效相对有限。靶向放射性核素治疗（TRT）可将低剂量辐射递送至多个转移灶，从而激发免疫刺激效应。然而，TRT与CAR T细胞联合治疗实体瘤的临床方案尚未建立。本研究旨在探讨镥-177（¹⁷⁷Lu）和锕-225（²²⁵Ac）产生的辐射对CAR T细胞体外活力及效应功能的影响，以评估该联合疗法的可行性。方法：使用不同剂量的¹⁷⁷Lu或²²⁵Ac辐射处理抗GD2 CAR T细胞后，通过流式细胞术检测其活力及对表达GD2的人源CHLA-20神经母细胞瘤和黑色素瘤M21细胞的杀伤活性。同时测定辐射后抗GD2 CAR T细胞中耗竭标志物PD-1、活化标志物CD69及激活受体NKG2D的表达水平。结果：¹⁷⁷Lu和²²⁵Ac均对抗GD2 CAR T细胞表现出剂量依赖性毒性。但无论辐射剂量与核素类型如何，辐射均能增强CAR T细胞对CHLA-20和M21细胞的杀伤活性。辐射后CAR T细胞中PD-1、CD69和NKG2D的表达均未发生显著变化。结论：在相同剂量下，¹⁷⁷Lu对CAR T细胞的活力影响更低，且两种核素均能增强其细胞毒性。因此，在评估体内联合治疗实体瘤的潜在协同效应时，基于¹⁷⁷Lu的TRT可能比基于²²⁵Ac的TRT更具优势。
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