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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...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society of Gene & Cell Therapy
2020
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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. |
format | Online Article Text |
id | pubmed-7191649 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | American Society of Gene & Cell Therapy |
record_format | MEDLINE/PubMed |
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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