背景:使用基因修饰的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治疗后复发,可能是由于修饰的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,已被建议掺入第四代CAR-T细胞以增强其持久性。然而,与该细胞因子相关的潜在全身毒性值得进一步评估.
方法:我们分析了持久性,表达膜结合IL15-IL15Rα嵌合蛋白(CD19/mbIL15qCAR-T)的抗小鼠CD19CAR-T细胞的抗肿瘤功效和潜在毒性,在用A20肿瘤细胞攻击的BALB/c小鼠以及NSG小鼠中。
结果:常规CD19CAR-T细胞在接受轻度淋巴清除方案(1Gy的全身照射(TBI))治疗的BALB/c小鼠中表现出低持久性和低疗效。CD19/mbIL15qCAR-T表现出延长的持久性和增强的体内功效,有效消除已建立的A20B细胞淋巴瘤。然而,这款CD19/MBIL15qCAR-T显示出重要的长期毒性,有明显的脾肿大,减肥,转氨酶升高,和一些组织中的显著炎症发现。CD19/mbIL15qCAR-T细胞转移后,小鼠的存活率高度受损,特别是如果在CAR-T细胞转移之前应用高TBI方案。
结论:栓系IL15-IL15Rα增强了CD19CAR-T细胞的抗肿瘤活性,但在免疫活性小鼠中表现出长期毒性。调节IL15-IL15Rα表达的诱导型系统可以被认为控制这种毒性。
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.