Image_3_Pre-sensitization of Malignant B Cells Through Venetoclax Significantly Improves the Cytotoxic Efficacy of CD19.CAR-T Cells.tif (33.44 kB)
Download file

Image_3_Pre-sensitization of Malignant B Cells Through Venetoclax Significantly Improves the Cytotoxic Efficacy of CD19.CAR-T Cells.tif

Download (33.44 kB)
figure
posted on 09.12.2020, 05:16 authored by 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, Anita Schmitt

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.

History

References