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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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Hauptverfasser: Yang, Mingya (VerfasserIn) , Wang, Lei (VerfasserIn) , Neuber, Brigitte (VerfasserIn) , Wang, Sanmei (VerfasserIn) , Sauer, Tim (VerfasserIn) , Sellner, Leopold (VerfasserIn) , Schubert, Maria-Luisa (VerfasserIn) , Hückelhoven-Krauss, Angela (VerfasserIn) , Kleist, Christian (VerfasserIn) , Eckstein, Volker (VerfasserIn) , Müller-Tidow, Carsten (VerfasserIn) , Dreger, Peter (VerfasserIn) , Schmitt, Michael (VerfasserIn) , Schmitt, Anita (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 09 December 2020
In: Frontiers in immunology
Year: 2020, Jahrgang: 11, Pages: 1-14
ISSN:1664-3224
DOI:10.3389/fimmu.2020.608167
Online-Zugang:Verlag, kostenfrei, Volltext: https://doi.org/10.3389/fimmu.2020.608167
Verlag, kostenfrei, Volltext: https://www.frontiersin.org/articles/10.3389/fimmu.2020.608167/full
Volltext
Verfasserangaben:Mingya Yang, Lei Wang, Ming Ni, Brigitte Neuber, Sanmei Wang, Wenjie Gong, Tim Sauer, Leopold Sellner, Maria-Luisa Schubert, Angela Hückelhoven-Krauss, Jian Hong, Lixin Zhu, Christian Kleist, Volker Eckstein, Carsten Müller-Tidow, Peter Dreger, Michael Schmitt and Anita Schmitt
Beschreibung
Zusammenfassung: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, and 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.
Beschreibung:Gesehen am 17.12.2020
Beschreibung:Online Resource
ISSN:1664-3224
DOI:10.3389/fimmu.2020.608167

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