Ablation of FAS confers allogeneic CD3– CAR T cells with resistance to rejection by T cells and natural killer cells

Silvia Menegatti; Sheila Lopez-Cobo; Aurelien Sutra Del Galy; Jaime Fuentealba; Lisseth Silva; Laetitia Perrin; Sandrine Heurtebise-Chrétien; Valentine Pottez-Jouatte; Aurelie Darbois; Nina Burgdorf; Anne Laure Privat; Albane Simon; Marguerite Laprie-Sentenac; Michael Saitakis; Bryce Wick; Beau R. Webber; Branden S. Moriarity; Olivier Lantz; Sebastian Amigorena; Laurie Menger

doi:10.1038/s41551-024-01282-8

Ablation of FAS confers allogeneic CD3^– CAR T cells with resistance to rejection by T cells and natural killer cells

Silvia Menegatti, Sheila Lopez-Cobo, Aurelien Sutra Del Galy, Jaime Fuentealba, Lisseth Silva, Laetitia Perrin, Sandrine Heurtebise-Chrétien, Valentine Pottez-Jouatte, Aurelie Darbois, Nina Burgdorf, Anne Laure Privat, Albane Simon, Marguerite Laprie-Sentenac, Michael Saitakis, Bryce Wick, Beau R. Webber, Branden S. Moriarity, Olivier Lantz, Sebastian Amigorena, Laurie Menger

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

2 Citations (Scopus)

Abstract

Allogeneic chimaeric antigen receptor T cells (allo-CAR T cells) derived from healthy donors could provide rapid access to standardized and affordable batches of therapeutic cells if their rejection by the host’s immune system is avoided. Here, by means of an in vivo genome-wide CRISPR knockout screen, we show that the deletion of Fas or B2m in allo- T cells increases their survival in immunocompetent mice. Human B2M^– allo-CAR T cells become highly sensitive to rejection mediated by natural killer (NK) cells, whereas FAS^– CAR T cells expressing normal levels of human leukocyte antigen I remain resistant to NK cells. CD3^–FAS^– CAR T cells outperformed CD3^–B2M^– CAR T cells in the control of leukaemia growth in mice under allogeneic pressure by T cells and NK cells. The partial protection of CD3^–FAS^– allo-CAR T cells from cellular rejection may improve the efficacy of allogeneic cellular therapies in patients with cancer.

Original language	English
Article number	5222
Pages (from-to)	1651-1664
Number of pages	14
Journal	Nature Biomedical Engineering
Volume	8
Issue number	12
DOIs	https://doi.org/10.1038/s41551-024-01282-8
Publication status	Published - 1 Dec 2024

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Menegatti, S., Lopez-Cobo, S., Sutra Del Galy, A., Fuentealba, J., Silva, L., Perrin, L., Heurtebise-Chrétien, S., Pottez-Jouatte, V., Darbois, A., Burgdorf, N., Privat, A. L., Simon, A., Laprie-Sentenac, M., Saitakis, M., Wick, B., Webber, B. R., Moriarity, B. S., Lantz, O., Amigorena, S., & Menger, L. (2024). Ablation of FAS confers allogeneic CD3^– CAR T cells with resistance to rejection by T cells and natural killer cells. Nature Biomedical Engineering, 8(12), 1651-1664. Article 5222. https://doi.org/10.1038/s41551-024-01282-8

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title = "Ablation of FAS confers allogeneic CD3– CAR T cells with resistance to rejection by T cells and natural killer cells",

abstract = "Allogeneic chimaeric antigen receptor T cells (allo-CAR T cells) derived from healthy donors could provide rapid access to standardized and affordable batches of therapeutic cells if their rejection by the host{\textquoteright}s immune system is avoided. Here, by means of an in vivo genome-wide CRISPR knockout screen, we show that the deletion of Fas or B2m in allo- T cells increases their survival in immunocompetent mice. Human B2M– allo-CAR T cells become highly sensitive to rejection mediated by natural killer (NK) cells, whereas FAS– CAR T cells expressing normal levels of human leukocyte antigen I remain resistant to NK cells. CD3–FAS– CAR T cells outperformed CD3–B2M– CAR T cells in the control of leukaemia growth in mice under allogeneic pressure by T cells and NK cells. The partial protection of CD3–FAS– allo-CAR T cells from cellular rejection may improve the efficacy of allogeneic cellular therapies in patients with cancer.",

author = "Silvia Menegatti and Sheila Lopez-Cobo and {Sutra Del Galy}, Aurelien and Jaime Fuentealba and Lisseth Silva and Laetitia Perrin and Sandrine Heurtebise-Chr{\'e}tien and Valentine Pottez-Jouatte and Aurelie Darbois and Nina Burgdorf and Privat, {Anne Laure} and Albane Simon and Marguerite Laprie-Sentenac and Michael Saitakis and Bryce Wick and Webber, {Beau R.} and Moriarity, {Branden S.} and Olivier Lantz and Sebastian Amigorena and Laurie Menger",

note = "Publisher Copyright: {\textcopyright} The Author(s), under exclusive licence to Springer Nature Limited 2024.",

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Menegatti, S, Lopez-Cobo, S, Sutra Del Galy, A, Fuentealba, J, Silva, L, Perrin, L, Heurtebise-Chrétien, S, Pottez-Jouatte, V, Darbois, A, Burgdorf, N, Privat, AL, Simon, A, Laprie-Sentenac, M, Saitakis, M, Wick, B, Webber, BR, Moriarity, BS, Lantz, O, Amigorena, S & Menger, L 2024, 'Ablation of FAS confers allogeneic CD3^– CAR T cells with resistance to rejection by T cells and natural killer cells', Nature Biomedical Engineering, vol. 8, no. 12, 5222, pp. 1651-1664. https://doi.org/10.1038/s41551-024-01282-8

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AU - Menegatti, Silvia

AU - Lopez-Cobo, Sheila

AU - Sutra Del Galy, Aurelien

AU - Fuentealba, Jaime

AU - Silva, Lisseth

AU - Perrin, Laetitia

AU - Heurtebise-Chrétien, Sandrine

AU - Pottez-Jouatte, Valentine

AU - Darbois, Aurelie

AU - Burgdorf, Nina

AU - Privat, Anne Laure

AU - Simon, Albane

AU - Laprie-Sentenac, Marguerite

AU - Saitakis, Michael

AU - Wick, Bryce

AU - Webber, Beau R.

AU - Moriarity, Branden S.

AU - Lantz, Olivier

AU - Amigorena, Sebastian

AU - Menger, Laurie

PY - 2024/12/1

Y1 - 2024/12/1

N2 - Allogeneic chimaeric antigen receptor T cells (allo-CAR T cells) derived from healthy donors could provide rapid access to standardized and affordable batches of therapeutic cells if their rejection by the host’s immune system is avoided. Here, by means of an in vivo genome-wide CRISPR knockout screen, we show that the deletion of Fas or B2m in allo- T cells increases their survival in immunocompetent mice. Human B2M– allo-CAR T cells become highly sensitive to rejection mediated by natural killer (NK) cells, whereas FAS– CAR T cells expressing normal levels of human leukocyte antigen I remain resistant to NK cells. CD3–FAS– CAR T cells outperformed CD3–B2M– CAR T cells in the control of leukaemia growth in mice under allogeneic pressure by T cells and NK cells. The partial protection of CD3–FAS– allo-CAR T cells from cellular rejection may improve the efficacy of allogeneic cellular therapies in patients with cancer.

AB - Allogeneic chimaeric antigen receptor T cells (allo-CAR T cells) derived from healthy donors could provide rapid access to standardized and affordable batches of therapeutic cells if their rejection by the host’s immune system is avoided. Here, by means of an in vivo genome-wide CRISPR knockout screen, we show that the deletion of Fas or B2m in allo- T cells increases their survival in immunocompetent mice. Human B2M– allo-CAR T cells become highly sensitive to rejection mediated by natural killer (NK) cells, whereas FAS– CAR T cells expressing normal levels of human leukocyte antigen I remain resistant to NK cells. CD3–FAS– CAR T cells outperformed CD3–B2M– CAR T cells in the control of leukaemia growth in mice under allogeneic pressure by T cells and NK cells. The partial protection of CD3–FAS– allo-CAR T cells from cellular rejection may improve the efficacy of allogeneic cellular therapies in patients with cancer.

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DO - 10.1038/s41551-024-01282-8

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SN - 2157-846X

VL - 8

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JO - Nature Biomedical Engineering

JF - Nature Biomedical Engineering

IS - 12

M1 - 5222

ER -

Ablation of FAS confers allogeneic CD3– CAR T cells with resistance to rejection by T cells and natural killer cells

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Ablation of FAS confers allogeneic CD3^– CAR T cells with resistance to rejection by T cells and natural killer cells