Interleukin-15-armored GPC3-CAR T cells for patients with solid cancers

Interleukin-15 (IL15) promotes the survival of T lymphocytes and enhances the antitumor properties of CAR T cells in preclinical models of solid neoplasms in which CAR T cells have limited efficacy1-4. Glypican-3 (GPC3) is expressed in a group of solid cancers5-10, and here we report the first evaluation in humans of the effects of IL15 co-expression on GPC3-CAR T cells. Cohort 1 patients (NCT02905188/NCT02932956) received GPC3-CAR T cells, which were safe but produced no objective antitumor responses and reached peak expansion at two weeks. Cohort 2 patients (NCT05103631/NCT04377932) received GPC3-CAR T cells that co-expressed IL15 (15.CAR), which mediated significantly increased cell expansion and induced a disease control rate of 66% and antitumor response rate of 33%. Infusion of 15.CAR T cells was associated with increased incidence of cytokine release syndrome, which was rapidly ameliorated by activation of the inducible caspase 9 safety switch. Compared to non-responders, tumor-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 genes related to type I interferon signaling. Collectively, these results demonstrate that IL15 increases the expansion, intratumoral survival, and antitumor activity of GPC3-CAR T cells in patients.

白细胞介素-15（Interleukin-15, IL15）可促进T淋巴细胞存活，并在CAR T细胞疗效有限的实体瘤临床前模型中增强嵌合抗原受体T细胞（chimeric antigen receptor T cell, CAR T）的抗肿瘤活性1-4。磷脂酰肌醇蛋白聚糖-3（Glypican-3, GPC3）在一类实体瘤中表达5-10；本研究首次在人体中评估了共表达IL15的GPC3靶向CAR T细胞的作用效果。队列1患者（临床试验编号：NCT02905188/NCT02932956）接受了GPC3-CAR T细胞治疗，该疗法安全性良好，但未产生客观抗肿瘤应答，且细胞扩增在两周时达到峰值。队列2患者（临床试验编号：NCT05103631/NCT04377932）接受了共表达IL15的GPC3-CAR T细胞（命名为15.CAR）治疗，该疗法可显著提升细胞扩增水平，疾病控制率达66%，客观抗肿瘤应答率达33%。输注15.CAR T细胞会增加细胞因子释放综合征（cytokine release syndrome, CRS）的发生风险，但该不良反应可通过激活诱导型半胱天冬酶9（inducible caspase 9）安全开关快速得到缓解。与无应答者相比，应答者的肿瘤浸润性15.CAR T细胞中，SWI/SNF表观遗传调控因子的表达受到抑制，而FOS、JUN家族基因以及与I型干扰素信号通路相关的基因表达则出现上调。综上，本研究结果证实，IL15可提升患者体内GPC3-CAR T细胞的扩增能力、肿瘤内存活能力以及抗肿瘤活性。