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

• 成果类型: Article
• 署名作者: 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
• 署名单位: Texas Children's Cancer Center; Baylor College of Medicine; Baylor College of Medicine; Baylor College of Medicine; Baylor College of Medicine; Baylor College Medical Hospital; Houston Methodist; Baylor College of Medicine; Baylor College Medical Hospital; Baylor College of Medicine; Baylor College of Medicine; University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia; University of Pennsylvania; University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia; University of Houston System; University of Houston; Baylor College of Medicine; University of North Carolina; University of North Carolina Chapel Hill; Baylor College of Medicine; Baylor College Medical Hospital
• 刊物名称: Nature
• ISSN/ISSBN: 0028-2395
• DOI: 10.1038/s41586-024-08261-8
• 发表日期: 2025-01-23
• 关键词: immunotherapeutic target; natural-killer; safety switch; glypican-3; tumors; overexpression; lymphocytes; expression; expansion; antibody

摘要

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 efficacy1-4. Glypican-3 (GPC3) is expressed in a group of solid cancers5-10, 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. We evaluate the effects in humans of interleukin-15 co-expression on glypican-3 (GPC3) chimeric antigen receptor (CAR) T cells and demonstrate that IL-15 increases the expansion, intratumoural survival and antitumour activity of GPC3 (expressed in a group of solid cancers) CAR T cells.