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; Andras Heczey

doi:10.1038/s41586-024-08261-8

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

Nature. 2024 Nov 27. doi: 10.1038/s41586-024-08261-8. Online ahead of print.

Authors

David Steffin^{1

2

3

4}, Nisha Ghatwai^{1

2}, Antonino Montalbano^{1

2}, Purva Rathi^{1

2}, Amy N Courtney^{1

2

3}, Azlann B Arnett^{2

5}, Julien Fleurence^{1

3}, Ramy Sweidan⁴, Tao Wang³, Huimin Zhang⁴, Prakash Masand⁶, John M Maris⁷, Daniel Martinez⁸, Jennifer Pogoriler⁸, Navin Varadarajan⁹, Sachin G Thakkar⁴, Deborah Lyon⁴, Natalia Lapteva^{4

10

11}, Mei Zhuyong⁴, Kalyani Patel¹¹, Dolores Lopez-Terrada¹¹, Carlos A Ramos^{3

4}, Premal Lulla^{3

4}, Tannaz Armaghany³, Bambi J Grilley^{1

2

3

4}, Stephen Gottschalk¹², Gianpietro Dotti¹³, Leonid S Metelitsa^{1

2

3

4}, Helen E Heslop^{3

4}, Malcolm K Brenner^{3

4}, Pavel Sumazin^{1

3}, Andras Heczey^{14

15

16

17

18}

Affiliations

¹ Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
² Center for Advanced Innate Cell Therapy, Baylor College of Medicine, Houston, TX, USA.
³ Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA.
⁴ Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital and Texas Children's Hospital, Houston, TX, USA.
⁵ Department of Immunology and Microbiology, Baylor College of Medicine, Houston, TX, USA.
⁶ Department of Radiology, Baylor College of Medicine, Houston, TX, USA.
⁷ Department of Pediatrics, Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
⁸ Pathology and Laboratory Medicine, Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
⁹ William A. Brookshire Department of Chemical and Biomolecular Engineering, University of Houston, Houston, TX, USA.
¹⁰ Pathology and Immunology Graduate Program, Baylor College of Medicine, Houston, TX, USA.
¹¹ Department of Pathology, Baylor College of Medicine, Houston, TX, USA.
¹² Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN, USA.
¹³ Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
¹⁴ Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA. [email protected].
¹⁵ Center for Advanced Innate Cell Therapy, Baylor College of Medicine, Houston, TX, USA. [email protected].
¹⁶ Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA. [email protected].
¹⁷ Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital and Texas Children's Hospital, Houston, TX, USA. [email protected].
¹⁸ Texas Children's Hospital Liver Tumor Program, Houston, TX, USA. [email protected].

PMID: 39604730
DOI: 10.1038/s41586-024-08261-8

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 efficacy^1-4. Glypican-3 (GPC3) is expressed in a group of solid cancers^5-10, 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.