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

David Steffin, Nisha Ghatwai, Antonino Montalbano, Purva Rathi, Amy N. Courtney, Azlann B. Arnett, Julien Fleurence, Ramy Sweidan, Tao Wang, Huimin Zhang, Prakash Masand, John M. Maris, Daniel Martinez, Jennifer Pogoriler, Navin Varadarajan, Sachin G. Thakkar, Deborah Lyon, Natalia Lapteva, Mei Zhuyong, Kalyani Patel, Dolores Lopez-Terrada, Carlos A. Ramos, Premal Lulla, Tannaz Armaghany, Bambi J. Grilley, Stephen Gottschalk, Gianpietro Dotti, Leonid S. Metelitsa, Helen E. Heslop, Malcolm K. Brenner, Pavel Sumazin and Andras Heczey ()
Additional contact information
David Steffin: Baylor College of Medicine
Nisha Ghatwai: Baylor College of Medicine
Antonino Montalbano: Baylor College of Medicine
Purva Rathi: Baylor College of Medicine
Amy N. Courtney: Baylor College of Medicine
Azlann B. Arnett: Baylor College of Medicine
Julien Fleurence: Baylor College of Medicine
Ramy Sweidan: Houston Methodist Hospital and Texas Children’s Hospital
Tao Wang: Baylor College of Medicine
Huimin Zhang: Houston Methodist Hospital and Texas Children’s Hospital
Prakash Masand: Baylor College of Medicine
John M. Maris: Children’s Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania
Daniel Martinez: Children’s Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania
Jennifer Pogoriler: Children’s Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania
Navin Varadarajan: University of Houston
Sachin G. Thakkar: Houston Methodist Hospital and Texas Children’s Hospital
Deborah Lyon: Houston Methodist Hospital and Texas Children’s Hospital
Natalia Lapteva: Houston Methodist Hospital and Texas Children’s Hospital
Mei Zhuyong: Houston Methodist Hospital and Texas Children’s Hospital
Kalyani Patel: Baylor College of Medicine
Dolores Lopez-Terrada: Baylor College of Medicine
Carlos A. Ramos: Baylor College of Medicine
Premal Lulla: Baylor College of Medicine
Tannaz Armaghany: Baylor College of Medicine
Bambi J. Grilley: Baylor College of Medicine
Stephen Gottschalk: St. Jude Children’s Research Hospital
Gianpietro Dotti: University of North Carolina
Leonid S. Metelitsa: Baylor College of Medicine
Helen E. Heslop: Baylor College of Medicine
Malcolm K. Brenner: Baylor College of Medicine
Pavel Sumazin: Baylor College of Medicine
Andras Heczey: Baylor College of Medicine

Nature, 2025, vol. 637, issue 8047, 940-946

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41586-024-08261-8

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