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

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 PatelDolores 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

Research output: Contribution to journal › Article › peer-review

12 Scopus citations

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, 2, 3–4}. Glypican-3 (GPC3) is expressed in a group of solid cancers^{5, 6, 7, 8, 9–10}, 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.

Original language	English (US)
Article number	550
Pages (from-to)	940-946
Number of pages	7
Journal	Nature
Volume	637
Issue number	8047
DOIs	https://doi.org/10.1038/s41586-024-08261-8
State	Published - Jan 23 2025

Keywords

Humans
Interleukin-15/metabolism
Glypicans/metabolism
Neoplasms/immunology
T-Lymphocytes/immunology
Female
Male
Receptors, Chimeric Antigen/immunology
Immunotherapy, Adoptive
Middle Aged
Cohort Studies
Adult
Aged
Cytokines/metabolism
Cell Proliferation

ASJC Scopus subject areas

General

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10.1038/s41586-024-08261-8

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Steffin, D., Ghatwai, N., Montalbano, A., Rathi, P., Courtney, A. N., Arnett, A. B., Fleurence, J., Sweidan, R., Wang, T., Zhang, H., Masand, P., Maris, J. M., Martinez, D., Pogoriler, J., Varadarajan, N., Thakkar, S. G., Lyon, D., Lapteva, N., Zhuyong, M., ... Heczey, A. (2025). Interleukin-15-armoured GPC3 CAR T cells for patients with solid cancers. Nature, 637(8047), 940-946. Article 550. https://doi.org/10.1038/s41586-024-08261-8

Steffin, D, Ghatwai, N, Montalbano, A, Rathi, P, Courtney, AN, Arnett, AB, Fleurence, J, Sweidan, R, Wang, T, Zhang, H, Masand, P, Maris, JM, Martinez, D, Pogoriler, J, Varadarajan, N, Thakkar, SG, Lyon, D, Lapteva, N, Zhuyong, M, Patel, K, Lopez-Terrada, D, Ramos, CA, Lulla, P, Armaghany, T, Grilley, BJ, Gottschalk, S, Dotti, G, Metelitsa, LS, Heslop, HE , Brenner, MK, Sumazin, P & Heczey, A 2025, 'Interleukin-15-armoured GPC3 CAR T cells for patients with solid cancers', Nature, vol. 637, no. 8047, 550, pp. 940-946. https://doi.org/10.1038/s41586-024-08261-8

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title = "Interleukin-15-armoured GPC3 CAR T cells for patients with solid cancers",

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, 2, 3–4. Glypican-3 (GPC3) is expressed in a group of solid cancers5, 6, 7, 8, 9–10, 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.",

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

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doi = "10.1038/s41586-024-08261-8",

language = "English (US)",

volume = "637",

pages = "940--946",

journal = "Nature",

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publisher = "Nature Research",

number = "8047",

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TY - JOUR

T1 - Interleukin-15-armoured GPC3 CAR T cells for patients with solid cancers

AU - Steffin, David

AU - Ghatwai, Nisha

AU - Montalbano, Antonino

AU - Rathi, Purva

AU - Courtney, Amy N.

AU - Arnett, Azlann B.

AU - Fleurence, Julien

AU - Sweidan, Ramy

AU - Wang, Tao

AU - Zhang, Huimin

AU - Masand, Prakash

AU - Maris, John M.

AU - Martinez, Daniel

AU - Pogoriler, Jennifer

AU - Varadarajan, Navin

AU - Thakkar, Sachin G.

AU - Lyon, Deborah

AU - Lapteva, Natalia

AU - Zhuyong, Mei

AU - Patel, Kalyani

AU - Lopez-Terrada, Dolores

AU - Ramos, Carlos A.

AU - Lulla, Premal

AU - Armaghany, Tannaz

AU - Grilley, Bambi J.

AU - Gottschalk, Stephen

AU - Dotti, Gianpietro

AU - Metelitsa, Leonid S.

AU - Heslop, Helen E.

AU - Brenner, Malcolm K.

AU - Sumazin, Pavel

AU - Heczey, Andras

PY - 2025/1/23

Y1 - 2025/1/23

N2 - 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, 2, 3–4. Glypican-3 (GPC3) is expressed in a group of solid cancers5, 6, 7, 8, 9–10, 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.

AB - 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, 2, 3–4. Glypican-3 (GPC3) is expressed in a group of solid cancers5, 6, 7, 8, 9–10, 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.

KW - Humans

KW - Interleukin-15/metabolism

KW - Glypicans/metabolism

KW - Neoplasms/immunology

KW - T-Lymphocytes/immunology

KW - Female

KW - Male

KW - Receptors, Chimeric Antigen/immunology

KW - Immunotherapy, Adoptive

KW - Middle Aged

KW - Cohort Studies

KW - Adult

KW - Aged

KW - Cytokines/metabolism

KW - Cell Proliferation

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U2 - 10.1038/s41586-024-08261-8

DO - 10.1038/s41586-024-08261-8

M3 - Article

C2 - 39604730

AN - SCOPUS:85210508893

SN - 0028-0836

VL - 637

SP - 940

EP - 946

JO - Nature

JF - Nature

IS - 8047

M1 - 550

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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