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Pre-sensitization of Malignant B Cells Through Venetoclax Significantly Improves the Cytotoxic Efficacy of CD19.CAR-T Cells

Chimeric antigen receptor (CAR) T cell therapy has shown promising responses in patients with refractory or relapsed aggressive B-cell malignancies that are resistant to conventional chemotherapy or stem cell transplantation. A potentially combinatorial therapeutic strategy may be the inhibition of...

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Autores principales: Yang, Mingya, Wang, Lei, Ni, Ming, Neuber, Brigitte, Wang, Sanmei, Gong, Wenjie, Sauer, Tim, Sellner, Leopold, Schubert, Maria-Luisa, Hückelhoven-Krauss, Angela, Hong, Jian, Zhu, Lixin, Kleist, Christian, Eckstein, Volker, Müller-Tidow, Carsten, Dreger, Peter, Schmitt, Michael, Schmitt, Anita
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756123/
https://www.ncbi.nlm.nih.gov/pubmed/33362794
http://dx.doi.org/10.3389/fimmu.2020.608167
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author Yang, Mingya
Wang, Lei
Ni, Ming
Neuber, Brigitte
Wang, Sanmei
Gong, Wenjie
Sauer, Tim
Sellner, Leopold
Schubert, Maria-Luisa
Hückelhoven-Krauss, Angela
Hong, Jian
Zhu, Lixin
Kleist, Christian
Eckstein, Volker
Müller-Tidow, Carsten
Dreger, Peter
Schmitt, Michael
Schmitt, Anita
author_facet Yang, Mingya
Wang, Lei
Ni, Ming
Neuber, Brigitte
Wang, Sanmei
Gong, Wenjie
Sauer, Tim
Sellner, Leopold
Schubert, Maria-Luisa
Hückelhoven-Krauss, Angela
Hong, Jian
Zhu, Lixin
Kleist, Christian
Eckstein, Volker
Müller-Tidow, Carsten
Dreger, Peter
Schmitt, Michael
Schmitt, Anita
author_sort Yang, Mingya
collection PubMed
description Chimeric antigen receptor (CAR) T cell therapy has shown promising responses in patients with refractory or relapsed aggressive B-cell malignancies that are resistant to conventional chemotherapy or stem cell transplantation. A potentially combinatorial therapeutic strategy may be the inhibition of anti-apoptotic Bcl-2 family proteins, overexpressed in most cancer cells. In this study we investigated the combination of 3rd-generation CD19.CAR-T cells and the BH3 mimetics venetoclax, a Bcl-2 inhibitor, or S63845, a Mcl-1 inhibitor, under three different treatment conditions: pre-sensitization of cancer cells with BH3 mimetics followed by CAR-T cell treatment, simultaneous combination therapy, and the administration of BH3 mimetics after CAR-T cell treatment. Our results showed that administration of CAR-T cells and BH3 mimetics had a significant effect on the quantity and quality of CD19.CAR-T cells. The administration of BH3 mimetics prior to CAR-T cell therapy exerted an enhanced cytotoxic efficacy by upregulating the CD19 expression and pro-apoptotic proteins in highly sensitive tumor cells, and thereby improving both CD19.CAR-T cell cytotoxicity and persistence. In simultaneous and post-treatment approaches, however, the quantity of CAR-T cells was adversely affected. Our findings indicate pre-sensitization of highly sensitive tumor cells with BH3 mimetics could enhance the cytotoxic efficacy of CAR-T cell treatment.
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spelling pubmed-77561232020-12-24 Pre-sensitization of Malignant B Cells Through Venetoclax Significantly Improves the Cytotoxic Efficacy of CD19.CAR-T Cells Yang, Mingya Wang, Lei Ni, Ming Neuber, Brigitte Wang, Sanmei Gong, Wenjie Sauer, Tim Sellner, Leopold Schubert, Maria-Luisa Hückelhoven-Krauss, Angela Hong, Jian Zhu, Lixin Kleist, Christian Eckstein, Volker Müller-Tidow, Carsten Dreger, Peter Schmitt, Michael Schmitt, Anita Front Immunol Immunology Chimeric antigen receptor (CAR) T cell therapy has shown promising responses in patients with refractory or relapsed aggressive B-cell malignancies that are resistant to conventional chemotherapy or stem cell transplantation. A potentially combinatorial therapeutic strategy may be the inhibition of anti-apoptotic Bcl-2 family proteins, overexpressed in most cancer cells. In this study we investigated the combination of 3rd-generation CD19.CAR-T cells and the BH3 mimetics venetoclax, a Bcl-2 inhibitor, or S63845, a Mcl-1 inhibitor, under three different treatment conditions: pre-sensitization of cancer cells with BH3 mimetics followed by CAR-T cell treatment, simultaneous combination therapy, and the administration of BH3 mimetics after CAR-T cell treatment. Our results showed that administration of CAR-T cells and BH3 mimetics had a significant effect on the quantity and quality of CD19.CAR-T cells. The administration of BH3 mimetics prior to CAR-T cell therapy exerted an enhanced cytotoxic efficacy by upregulating the CD19 expression and pro-apoptotic proteins in highly sensitive tumor cells, and thereby improving both CD19.CAR-T cell cytotoxicity and persistence. In simultaneous and post-treatment approaches, however, the quantity of CAR-T cells was adversely affected. Our findings indicate pre-sensitization of highly sensitive tumor cells with BH3 mimetics could enhance the cytotoxic efficacy of CAR-T cell treatment. Frontiers Media S.A. 2020-12-09 /pmc/articles/PMC7756123/ /pubmed/33362794 http://dx.doi.org/10.3389/fimmu.2020.608167 Text en Copyright © 2020 Yang, Wang, Ni, Neuber, Wang, Gong, Sauer, Sellner, Schubert, Hückelhoven-Krauss, Hong, Zhu, Kleist, Eckstein, Müller-Tidow, Dreger, Schmitt and Schmitt http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Yang, Mingya
Wang, Lei
Ni, Ming
Neuber, Brigitte
Wang, Sanmei
Gong, Wenjie
Sauer, Tim
Sellner, Leopold
Schubert, Maria-Luisa
Hückelhoven-Krauss, Angela
Hong, Jian
Zhu, Lixin
Kleist, Christian
Eckstein, Volker
Müller-Tidow, Carsten
Dreger, Peter
Schmitt, Michael
Schmitt, Anita
Pre-sensitization of Malignant B Cells Through Venetoclax Significantly Improves the Cytotoxic Efficacy of CD19.CAR-T Cells
title Pre-sensitization of Malignant B Cells Through Venetoclax Significantly Improves the Cytotoxic Efficacy of CD19.CAR-T Cells
title_full Pre-sensitization of Malignant B Cells Through Venetoclax Significantly Improves the Cytotoxic Efficacy of CD19.CAR-T Cells
title_fullStr Pre-sensitization of Malignant B Cells Through Venetoclax Significantly Improves the Cytotoxic Efficacy of CD19.CAR-T Cells
title_full_unstemmed Pre-sensitization of Malignant B Cells Through Venetoclax Significantly Improves the Cytotoxic Efficacy of CD19.CAR-T Cells
title_short Pre-sensitization of Malignant B Cells Through Venetoclax Significantly Improves the Cytotoxic Efficacy of CD19.CAR-T Cells
title_sort pre-sensitization of malignant b cells through venetoclax significantly improves the cytotoxic efficacy of cd19.car-t cells
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756123/
https://www.ncbi.nlm.nih.gov/pubmed/33362794
http://dx.doi.org/10.3389/fimmu.2020.608167
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