Cargando…
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...
Autores principales: | , , , , , , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1783626472905244672 |
---|---|
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. |
format | Online Article Text |
id | pubmed-7756123 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT yangmingya presensitizationofmalignantbcellsthroughvenetoclaxsignificantlyimprovesthecytotoxicefficacyofcd19cartcells AT wanglei presensitizationofmalignantbcellsthroughvenetoclaxsignificantlyimprovesthecytotoxicefficacyofcd19cartcells AT niming presensitizationofmalignantbcellsthroughvenetoclaxsignificantlyimprovesthecytotoxicefficacyofcd19cartcells AT neuberbrigitte presensitizationofmalignantbcellsthroughvenetoclaxsignificantlyimprovesthecytotoxicefficacyofcd19cartcells AT wangsanmei presensitizationofmalignantbcellsthroughvenetoclaxsignificantlyimprovesthecytotoxicefficacyofcd19cartcells AT gongwenjie presensitizationofmalignantbcellsthroughvenetoclaxsignificantlyimprovesthecytotoxicefficacyofcd19cartcells AT sauertim presensitizationofmalignantbcellsthroughvenetoclaxsignificantlyimprovesthecytotoxicefficacyofcd19cartcells AT sellnerleopold presensitizationofmalignantbcellsthroughvenetoclaxsignificantlyimprovesthecytotoxicefficacyofcd19cartcells AT schubertmarialuisa presensitizationofmalignantbcellsthroughvenetoclaxsignificantlyimprovesthecytotoxicefficacyofcd19cartcells AT huckelhovenkraussangela presensitizationofmalignantbcellsthroughvenetoclaxsignificantlyimprovesthecytotoxicefficacyofcd19cartcells AT hongjian presensitizationofmalignantbcellsthroughvenetoclaxsignificantlyimprovesthecytotoxicefficacyofcd19cartcells AT zhulixin presensitizationofmalignantbcellsthroughvenetoclaxsignificantlyimprovesthecytotoxicefficacyofcd19cartcells AT kleistchristian presensitizationofmalignantbcellsthroughvenetoclaxsignificantlyimprovesthecytotoxicefficacyofcd19cartcells AT ecksteinvolker presensitizationofmalignantbcellsthroughvenetoclaxsignificantlyimprovesthecytotoxicefficacyofcd19cartcells AT mullertidowcarsten presensitizationofmalignantbcellsthroughvenetoclaxsignificantlyimprovesthecytotoxicefficacyofcd19cartcells AT dregerpeter presensitizationofmalignantbcellsthroughvenetoclaxsignificantlyimprovesthecytotoxicefficacyofcd19cartcells AT schmittmichael presensitizationofmalignantbcellsthroughvenetoclaxsignificantlyimprovesthecytotoxicefficacyofcd19cartcells AT schmittanita presensitizationofmalignantbcellsthroughvenetoclaxsignificantlyimprovesthecytotoxicefficacyofcd19cartcells |