Steffin David, Ghatwai Nisha, Montalbano Antonino, Rathi Purva, Courtney Amy N, Arnett Azlann B, Fleurence Julien, Sweidan Ramy, Wang Tao, Zhang Huimin, Masand Prakash, Maris John M, Martinez Daniel, Pogoriler Jennifer, Varadarajan Navin, Thakkar Sachin G, Lyon Deborah, Lapteva Natalia, Zhuyong Mei, Patel Kalyani, Lopez-Terrada Dolores, Ramos Carlos A, Lulla Premal, Armaghany Tannaz, Grilley Bambi J, Gottschalk Stephen, Dotti Gianpietro, Metelitsa Leonid S, Heslop Helen E, Brenner Malcolm K, Sumazin Pavel, Heczey Andras
Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
Center for Advanced Innate Cell Therapy, Baylor College of Medicine, Houston, TX, USA.
Nature. 2025 Jan;637(8047):940-946. doi: 10.1038/s41586-024-08261-8. Epub 2024 Nov 27.
Interleukin-15 (IL-15) promotes the survival of T lymphocytes and enhances the antitumour properties of chimeric antigen receptor (CAR) T cells in preclinical models of solid neoplasms in which CAR T cells have limited efficacy. Glypican-3 (GPC3) is expressed in a group of solid cancers, and here we report the evaluation in humans of the effects of IL-15 co-expression on GPC3-expressing CAR T cells (hereafter GPC3 CAR T cells). Cohort 1 patients ( NCT02905188 and NCT02932956 ) received GPC3 CAR T cells, which were safe but produced no objective antitumour responses and reached peak expansion at 2 weeks. Cohort 2 patients ( NCT05103631 and NCT04377932 ) received GPC3 CAR T cells that co-expressed IL-15 (15.CAR), which mediated significantly increased cell expansion and induced a disease control rate of 66% and antitumour response rate of 33%. Infusion of 15.CAR T cells was associated with increased incidence of cytokine release syndrome, which was controlled with IL-1/IL-6 blockade or rapidly ameliorated by activation of the inducible caspase 9 safety switch. Compared with non-responders, tumour-infiltrating 15.CAR T cells from responders showed repression of SWI/SNF epigenetic regulators and upregulation of FOS and JUN family members, as well as of genes related to type I interferon signalling. Collectively, these results demonstrate that IL-15 increases the expansion, intratumoural survival and antitumour activity of GPC3 CAR T cells in patients.
白细胞介素-15（IL-15）可促进T淋巴细胞存活，并在实体瘤临床前模型中增强嵌合抗原受体（CAR）T细胞的抗肿瘤特性，而在这些模型中CAR T细胞的疗效有限。磷脂酰肌醇蛋白聚糖-3（GPC3）在一组实体癌中表达，在此我们报告了IL-15共表达对表达GPC3的CAR T细胞（以下简称GPC3 CAR T细胞）在人体中的作用评估。队列1患者（NCT02905188和NCT02932956）接受了GPC3 CAR T细胞，这些细胞是安全的，但未产生客观的抗肿瘤反应，且在2周时达到扩增峰值。队列2患者（NCT05103631和NCT04377932）接受了共表达IL-15的GPC3 CAR T细胞（15.CAR），其介导细胞扩增显著增加，并诱导了66%的疾病控制率和33%的抗肿瘤反应率。输注15.CAR T细胞与细胞因子释放综合征发生率增加相关，该综合征可通过IL-1/IL-6阻断得到控制，或通过激活诱导型半胱天冬酶9安全开关迅速改善。与无反应者相比，反应者的肿瘤浸润15.CAR T细胞显示出SWI/SNF表观遗传调节因子的抑制以及FOS和JUN家族成员以及与I型干扰素信号相关基因的上调。总体而言，这些结果表明IL-15可增加患者体内GPC3 CAR T细胞的扩增、肿瘤内存活和抗肿瘤活性。
