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A Cross-Reactive Small Protein Binding Domain Provides a Model to Study Off-Tumor CAR-T Cell Toxicity

Tumor-targeted chimeric antigen receptor (CAR)-engineered T lymphocytes (CAR-T cells) have demonstrated striking clinical success, but their use has been associated with a constellation of toxicities. A better understanding of the pathogenesis of these toxicities is required to improve the safety pr...

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Autores principales: Hammill, Joanne A., Kwiecien, Jacek M., Dvorkin-Gheva, Anna, Lau, Vivian W.C., Baker, Christopher, Wu, Ying, Bezverbnaya, Ksenia, Aarts, Craig, Heslen, Christopher W., Denisova, Galina F., Derocher, Heather, Milne, Katy, Nelson, Brad H., Bramson, Jonathan L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191649/
https://www.ncbi.nlm.nih.gov/pubmed/32368616
http://dx.doi.org/10.1016/j.omto.2020.04.001
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author Hammill, Joanne A.
Kwiecien, Jacek M.
Dvorkin-Gheva, Anna
Lau, Vivian W.C.
Baker, Christopher
Wu, Ying
Bezverbnaya, Ksenia
Aarts, Craig
Heslen, Christopher W.
Denisova, Galina F.
Derocher, Heather
Milne, Katy
Nelson, Brad H.
Bramson, Jonathan L.
author_facet Hammill, Joanne A.
Kwiecien, Jacek M.
Dvorkin-Gheva, Anna
Lau, Vivian W.C.
Baker, Christopher
Wu, Ying
Bezverbnaya, Ksenia
Aarts, Craig
Heslen, Christopher W.
Denisova, Galina F.
Derocher, Heather
Milne, Katy
Nelson, Brad H.
Bramson, Jonathan L.
author_sort Hammill, Joanne A.
collection PubMed
description Tumor-targeted chimeric antigen receptor (CAR)-engineered T lymphocytes (CAR-T cells) have demonstrated striking clinical success, but their use has been associated with a constellation of toxicities. A better understanding of the pathogenesis of these toxicities is required to improve the safety profile of CAR-T cells. Herein, we describe a xenograft model of off-tumor CAR-T cell-associated toxicity. Human CAR-T cells targeted against HER2 using a small-protein binding domain induced acute, dose-dependent toxicities in mice. The inclusion of a CD28 or 4-1BB co-stimulatory domain in the CAR was required to produce toxicity; however, co-stimulation through CD28 was most toxic on a per-cell basis. CAR-T cell activation in the lungs and heart was associated with a systemic cytokine storm. The severity of observed toxicities was dependent upon the peripheral blood mononuclear cell (PBMC) donor used as a T cell source and paralleled the CD4(+)-to-CD8(+) T cell ratio in the adoptive transfer product. CD4(+) CAR-T cells were determined to be the primary contributors to CAR-T cell-associated toxicity. However, donor-specific differences persisted after infusion of a purified CD4(+) CAR-T cell product, indicating a role for additional variables. This work highlights the contributions of CAR-T cell-intrinsic variables to the pathogenesis of off-tumor toxicity.
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spelling pubmed-71916492020-05-04 A Cross-Reactive Small Protein Binding Domain Provides a Model to Study Off-Tumor CAR-T Cell Toxicity Hammill, Joanne A. Kwiecien, Jacek M. Dvorkin-Gheva, Anna Lau, Vivian W.C. Baker, Christopher Wu, Ying Bezverbnaya, Ksenia Aarts, Craig Heslen, Christopher W. Denisova, Galina F. Derocher, Heather Milne, Katy Nelson, Brad H. Bramson, Jonathan L. Mol Ther Oncolytics Article Tumor-targeted chimeric antigen receptor (CAR)-engineered T lymphocytes (CAR-T cells) have demonstrated striking clinical success, but their use has been associated with a constellation of toxicities. A better understanding of the pathogenesis of these toxicities is required to improve the safety profile of CAR-T cells. Herein, we describe a xenograft model of off-tumor CAR-T cell-associated toxicity. Human CAR-T cells targeted against HER2 using a small-protein binding domain induced acute, dose-dependent toxicities in mice. The inclusion of a CD28 or 4-1BB co-stimulatory domain in the CAR was required to produce toxicity; however, co-stimulation through CD28 was most toxic on a per-cell basis. CAR-T cell activation in the lungs and heart was associated with a systemic cytokine storm. The severity of observed toxicities was dependent upon the peripheral blood mononuclear cell (PBMC) donor used as a T cell source and paralleled the CD4(+)-to-CD8(+) T cell ratio in the adoptive transfer product. CD4(+) CAR-T cells were determined to be the primary contributors to CAR-T cell-associated toxicity. However, donor-specific differences persisted after infusion of a purified CD4(+) CAR-T cell product, indicating a role for additional variables. This work highlights the contributions of CAR-T cell-intrinsic variables to the pathogenesis of off-tumor toxicity. American Society of Gene & Cell Therapy 2020-04-14 /pmc/articles/PMC7191649/ /pubmed/32368616 http://dx.doi.org/10.1016/j.omto.2020.04.001 Text en © 2020 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Hammill, Joanne A.
Kwiecien, Jacek M.
Dvorkin-Gheva, Anna
Lau, Vivian W.C.
Baker, Christopher
Wu, Ying
Bezverbnaya, Ksenia
Aarts, Craig
Heslen, Christopher W.
Denisova, Galina F.
Derocher, Heather
Milne, Katy
Nelson, Brad H.
Bramson, Jonathan L.
A Cross-Reactive Small Protein Binding Domain Provides a Model to Study Off-Tumor CAR-T Cell Toxicity
title A Cross-Reactive Small Protein Binding Domain Provides a Model to Study Off-Tumor CAR-T Cell Toxicity
title_full A Cross-Reactive Small Protein Binding Domain Provides a Model to Study Off-Tumor CAR-T Cell Toxicity
title_fullStr A Cross-Reactive Small Protein Binding Domain Provides a Model to Study Off-Tumor CAR-T Cell Toxicity
title_full_unstemmed A Cross-Reactive Small Protein Binding Domain Provides a Model to Study Off-Tumor CAR-T Cell Toxicity
title_short A Cross-Reactive Small Protein Binding Domain Provides a Model to Study Off-Tumor CAR-T Cell Toxicity
title_sort cross-reactive small protein binding domain provides a model to study off-tumor car-t cell toxicity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191649/
https://www.ncbi.nlm.nih.gov/pubmed/32368616
http://dx.doi.org/10.1016/j.omto.2020.04.001
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