Metabolic engineering against the arginine microenvironment enhances CAR-T cell proliferation and therapeutic activity

Livingstone Fultang; Sarah Booth; Orli Yogev; Barbara Martins da Costa; Vanessa Tubb; Silvia Panetti; Victoria Stavrou; Ugo Scarpa; Andris Jankevics; Gavin Lloyd; Andrew D Southam; Steven P. Lee; Warwick Dunn; Louis Chesler; Francis Jay Mussai; Carmela De Santo

doi:10.1182/blood.2019004500

Metabolic engineering against the arginine microenvironment enhances CAR-T cell proliferation and therapeutic activity

Livingstone Fultang, Sarah Booth, Orli Yogev, Barbara Martins da Costa, Vanessa Tubb, Silvia Panetti, Victoria Stavrou, Ugo Scarpa, Andris Jankevics, Gavin Lloyd, Andrew D Southam, Steven P. Lee, Warwick Dunn, Louis Chesler, Francis Jay Mussai, Carmela De Santo

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

13 Citations (Scopus)

Abstract

Hematological and solid cancers catabolize the semiessential amino acid arginine to drive cell proliferation. However, the resulting low arginine microenvironment also impairs chimeric antigen receptor T cells (CAR-T) cell proliferation, limiting their efficacy in clinical trials against hematological and solid malignancies. T cells are susceptible to the low arginine microenvironment because of the low expression of the arginine resynthesis enzymes argininosuccinate synthase (ASS) and ornithine transcarbamylase (OTC). We demonstrate that T cells can be reengineered to express functional ASS or OTC enzymes, in concert with different chimeric antigen receptors. Enzyme modifications increase CAR-T cell proliferation, with no loss of CAR cytotoxicity or increased exhaustion. In vivo, enzyme-modified CAR-T cells lead to enhanced clearance of leukemia or solid tumor burden, providing the first metabolic modification to enhance CAR-T cell therapies.

Original language	English
Pages (from-to)	1155-1160
Number of pages	6
Journal	Blood
Issue number	10
DOIs	https://doi.org/10.1182/blood.2019004500
Publication status	Published - 3 Sept 2020

Bibliographical note

Funding Information:
This work was supported by Cancer Research UK, Treating Children with Cancer, Amber Phillpott Trust, Birmingham Children’s Hospital, and the alumni and donors to the University of Birmingham. This work was supported by Phenome Centre Birmingham (MR/M009157/1).

Publisher Copyright:
© 2020 by The American Society of Hematology

ASJC Scopus subject areas

Biochemistry
Immunology
Hematology
Cell Biology

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10.1182/blood.2019004500

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Fultang, L., Booth, S., Yogev, O., Costa, B. M. D., Tubb, V., Panetti, S., Stavrou, V., Scarpa, U., Jankevics, A., Lloyd, G., Southam, A. D., Lee, S. P., Dunn, W., Chesler, L., Mussai, F. J., & Santo, C. D. (2020). Metabolic engineering against the arginine microenvironment enhances CAR-T cell proliferation and therapeutic activity. Blood, (10), 1155-1160. https://doi.org/10.1182/blood.2019004500

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title = "Metabolic engineering against the arginine microenvironment enhances CAR-T cell proliferation and therapeutic activity",

abstract = "Hematological and solid cancers catabolize the semiessential amino acid arginine to drive cell proliferation. However, the resulting low arginine microenvironment also impairs chimeric antigen receptor T cells (CAR-T) cell proliferation, limiting their efficacy in clinical trials against hematological and solid malignancies. T cells are susceptible to the low arginine microenvironment because of the low expression of the arginine resynthesis enzymes argininosuccinate synthase (ASS) and ornithine transcarbamylase (OTC). We demonstrate that T cells can be reengineered to express functional ASS or OTC enzymes, in concert with different chimeric antigen receptors. Enzyme modifications increase CAR-T cell proliferation, with no loss of CAR cytotoxicity or increased exhaustion. In vivo, enzyme-modified CAR-T cells lead to enhanced clearance of leukemia or solid tumor burden, providing the first metabolic modification to enhance CAR-T cell therapies.",

author = "Livingstone Fultang and Sarah Booth and Orli Yogev and Costa, {Barbara Martins da} and Vanessa Tubb and Silvia Panetti and Victoria Stavrou and Ugo Scarpa and Andris Jankevics and Gavin Lloyd and Southam, {Andrew D} and Lee, {Steven P.} and Warwick Dunn and Louis Chesler and Mussai, {Francis Jay} and Santo, {Carmela De}",

note = "Funding Information: This work was supported by Cancer Research UK, Treating Children with Cancer, Amber Phillpott Trust, Birmingham Children{\textquoteright}s Hospital, and the alumni and donors to the University of Birmingham. This work was supported by Phenome Centre Birmingham (MR/M009157/1). Publisher Copyright: {\textcopyright} 2020 by The American Society of Hematology",

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Fultang, L, Booth, S, Yogev, O, Costa, BMD, Tubb, V, Panetti, S, Stavrou, V, Scarpa, U, Jankevics, A, Lloyd, G , Southam, AD, Lee, SP, Dunn, W, Chesler, L, Mussai, FJ & Santo, CD 2020, 'Metabolic engineering against the arginine microenvironment enhances CAR-T cell proliferation and therapeutic activity', Blood, no. 10, pp. 1155-1160. https://doi.org/10.1182/blood.2019004500

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T1 - Metabolic engineering against the arginine microenvironment enhances CAR-T cell proliferation and therapeutic activity

AU - Fultang, Livingstone

AU - Booth, Sarah

AU - Yogev, Orli

AU - Costa, Barbara Martins da

AU - Tubb, Vanessa

AU - Panetti, Silvia

AU - Stavrou, Victoria

AU - Scarpa, Ugo

AU - Jankevics, Andris

AU - Lloyd, Gavin

AU - Southam, Andrew D

AU - Lee, Steven P.

AU - Dunn, Warwick

AU - Chesler, Louis

AU - Mussai, Francis Jay

AU - Santo, Carmela De

N1 - Funding Information: This work was supported by Cancer Research UK, Treating Children with Cancer, Amber Phillpott Trust, Birmingham Children’s Hospital, and the alumni and donors to the University of Birmingham. This work was supported by Phenome Centre Birmingham (MR/M009157/1). Publisher Copyright: © 2020 by The American Society of Hematology

PY - 2020/9/3

Y1 - 2020/9/3

N2 - Hematological and solid cancers catabolize the semiessential amino acid arginine to drive cell proliferation. However, the resulting low arginine microenvironment also impairs chimeric antigen receptor T cells (CAR-T) cell proliferation, limiting their efficacy in clinical trials against hematological and solid malignancies. T cells are susceptible to the low arginine microenvironment because of the low expression of the arginine resynthesis enzymes argininosuccinate synthase (ASS) and ornithine transcarbamylase (OTC). We demonstrate that T cells can be reengineered to express functional ASS or OTC enzymes, in concert with different chimeric antigen receptors. Enzyme modifications increase CAR-T cell proliferation, with no loss of CAR cytotoxicity or increased exhaustion. In vivo, enzyme-modified CAR-T cells lead to enhanced clearance of leukemia or solid tumor burden, providing the first metabolic modification to enhance CAR-T cell therapies.

AB - Hematological and solid cancers catabolize the semiessential amino acid arginine to drive cell proliferation. However, the resulting low arginine microenvironment also impairs chimeric antigen receptor T cells (CAR-T) cell proliferation, limiting their efficacy in clinical trials against hematological and solid malignancies. T cells are susceptible to the low arginine microenvironment because of the low expression of the arginine resynthesis enzymes argininosuccinate synthase (ASS) and ornithine transcarbamylase (OTC). We demonstrate that T cells can be reengineered to express functional ASS or OTC enzymes, in concert with different chimeric antigen receptors. Enzyme modifications increase CAR-T cell proliferation, with no loss of CAR cytotoxicity or increased exhaustion. In vivo, enzyme-modified CAR-T cells lead to enhanced clearance of leukemia or solid tumor burden, providing the first metabolic modification to enhance CAR-T cell therapies.

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DO - 10.1182/blood.2019004500

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EP - 1160

JO - Blood

JF - Blood

IS - 10

ER -

Metabolic engineering against the arginine microenvironment enhances CAR-T cell proliferation and therapeutic activity

Abstract

Bibliographical note

ASJC Scopus subject areas

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