美国贝勒医学院Andras Heczey小组发现，白介素-15装配的GPC3 CAR T细胞可用于实体瘤患者。相关论文于2024年11月27日在线发表在《自然》杂志上。

研究人员表示，白介素-15（IL-15）能够促进T淋巴细胞的生存，并增强嵌合抗原受体（CAR）T细胞在前临床模型中对实体瘤的抗肿瘤特性。但在这些模型中，CAR T细胞的疗效有限。

糖皮质蛋白-3（GPC3）在一类实体瘤中表达，研究人员报告了IL-15共表达对GPC3表达的CAR T细胞（以下简称GPC3 CAR T细胞）在人类中的影响评估。1组患者（NCT02905188和NCT02932956）接受了GPC3 CAR T细胞治疗，治疗是安全的，但未产生明显的抗肿瘤反应，且在2周时达到峰值扩增。

2组患者（NCT05103631和NCT04377932）接受了共表达IL-15的GPC3 CAR T细胞（15.CAR），该治疗显著增加了细胞扩增，并诱导了66%的疾病控制率和33%的抗肿瘤反应率。15.CAR T细胞输注与细胞因子释放综合症的发生率增加相关，该副作用通过IL-1/IL-6阻断，或通过激活诱导型半胱天冬酶9安全开关迅速缓解。

与无反应者相比，来自反应者的肿瘤浸润性15.CAR T细胞显示出，SWI/SNF表观遗传调控因子的抑制和FOS及JUN家族成员的上调，以及与I型干扰素信号相关基因的上调。

综合来看，这些结果表明，IL-15增强了GPC3 CAR T细胞在患者中的，扩增、肿瘤内生存和抗肿瘤活性。

附：英文原文

Title: Interleukin-15-armoured GPC3 CAR T cells for patients with solid cancers

Author: 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

Issue&Volume: 2024-11-27

Abstract: Interleukin-15 (IL-15) promotes the survival of Tlymphocytes and enhances the antitumour properties of chimeric antigen receptor (CAR) Tcells in preclinical models of solid neoplasms in which CAR Tcells have limited efficacy1,2,3,4. Glypican-3 (GPC3) is expressed in a group of solid cancers5,6,7,8,9,10, and here we report the evaluation in humans of the effects of IL-15 co-expression on GPC3-expressing CAR Tcells (hereafter GPC3 CAR T cells). Cohort1 patients (NCT02905188 and NCT02932956) received GPC3 CAR Tcells, which were safe but produced no objective antitumour responses and reached peak expansion at 2weeks. Cohort2 patients (NCT05103631 and NCT04377932) received GPC3 CAR Tcells 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 Tcells 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 caspase9 safety switch. Compared with non-responders, tumour-infiltrating 15.CAR Tcells from responders showed repression of SWI/SNF epigenetic regulators and upregulation of FOS and JUN family members, as well as of genes related to typeI interferon signalling. Collectively, these results demonstrate that IL-15 increases the expansion, intratumoural survival and antitumour activity of GPC3 CAR Tcells in patients.

DOI: 10.1038/s41586-024-08261-8

Source: https://www.nature.com/articles/s41586-024-08261-8