使用转基因 T 细胞表达嵌合抗原受体 (CAR-T) 的过继细胞疗法已显示出令人鼓舞的结果，特别是在某些血癌中。然而，超过 40% 的 B 细胞恶性肿瘤患者在 CAR-T 治疗后会出现复发，这可能是由于修饰后的 T 细胞在体内的持久性不足。 IL15 以其促生存和增殖特性而闻名，已建议将其纳入第四代 CAR-T 细胞中以增强其持久性。然而，与该细胞因子相关的潜在全身毒性值得进一步评估。我们分析了表达膜结合 IL15-IL15Rα 嵌合蛋白（CD19/mbIL15q CAR-）的抗小鼠 CD19 CAR-T 细胞的持久性、抗肿瘤功效和潜在毒性。 T），在用 A20 肿瘤细胞攻击的 BALB/c 小鼠以及 NSG 小鼠中。传统 CD19 CAR-T 细胞在接受轻度淋巴细胞清除方案（全身照射 (TBI) 治疗）的 BALB/c 小鼠中表现出持久性低且疗效差1 戈瑞）。 CD19/mbIL15q CAR-T 表现出持久的持久性和增强的体内功效，有效消除已形成的 A20 B 细胞淋巴瘤。然而，这种 CD19/mbIL15q CAR-T 显示出重要的长期毒性，包括明显的脾肿大、体重减轻、转氨酶升高以及某些组织中明显的炎症表现。 CD19/mbIL15q CAR-T 细胞转移后，小鼠的存活率受到严重影响，特别是在 CAR-T 细胞转移前应用高 TBI 方案时。拴系的 IL15-IL15Rα 增强了 CD19 CAR-T 细胞的抗肿瘤活性，但表现出长期毒性在免疫功能正常的小鼠中。可以考虑调节 IL15-IL15Rα 表达的诱导系统来控制这种毒性。© 作者（或其雇主）2024。根据 CC BY-NC 允许重复使用。禁止商业再利用。请参阅权利和权限。英国医学杂志出版。

Adoptive cell therapy using genetically modified T cells to express chimeric antigen receptors (CAR-T) has shown encouraging results, particularly in certain blood cancers. Nevertheless, over 40% of B cell malignancy patients experience a relapse after CAR-T therapy, likely due to inadequate persistence of the modified T cells in the body. IL15, known for its pro-survival and proliferative properties, has been suggested for incorporation into the fourth generation of CAR-T cells to enhance their persistence. However, the potential systemic toxicity associated with this cytokine warrants further evaluation.We analyzed the persistence, antitumor efficacy and potential toxicity of anti-mouse CD19 CAR-T cells which express a membrane-bound IL15-IL15Rα chimeric protein (CD19/mbIL15q CAR-T), in BALB/c mice challenged with A20 tumor cells as well as in NSG mice.Conventional CD19 CAR-T cells showed low persistence and poor efficacy in BALB/c mice treated with mild lymphodepletion regimens (total body irradiation (TBI) of 1 Gy). CD19/mbIL15q CAR-T exhibits prolonged persistence and enhanced in vivo efficacy, effectively eliminating established A20 B cell lymphoma. However, this CD19/mbIL15q CAR-T displays important long-term toxicities, with marked splenomegaly, weight loss, transaminase elevations, and significant inflammatory findings in some tissues. Mice survival is highly compromised after CD19/mbIL15q CAR-T cell transfer, particularly if a high TBI regimen is applied before CAR-T cell transfer.Tethered IL15-IL15Rα augments the antitumor activity of CD19 CAR-T cells but displays long-term toxicity in immunocompetent mice. Inducible systems to regulate IL15-IL15Rα expression could be considered to control this toxicity.© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.