作者: Lulla, Premal ; Courtney, Amy N ; Mei, Zhuyong ; Lopez-Terrada, Dolores ; Ramos, Carlos ; Metelitsa, Leonid S ; Heslop, Helen E ; Armaghany, Tannaz ; Pogoriler, Jennifer ; Ghatwai, Nisha ; Martinez, Daniel ; Arnett, Azlann B ; Grilley, Bambi J ; Montalbano, Antonino ; Steffin, David ; Rathi, Purva ; Heczey, Andras ; Lapteva, Natasha ; Zhang, Huimin ; Wang, Thao ; Dotti, Gianpietro ; Thakkar, Sachin G ; Maris, John M ; Brenner, Malcolm K ; Varadarajan, Navin ; Masand, Prakash ; Patel, Kalyani ; Fleurence, Julien ; Sumazin, Pavel ; Sweidan, Ramy ; Lyon, Deborah
AbstractInterleukin-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.