Frontiers in Immunology (Dec 2020)

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

  • Mingya Yang,
  • Mingya Yang,
  • Lei Wang,
  • Ming Ni,
  • Ming Ni,
  • Brigitte Neuber,
  • Sanmei Wang,
  • Sanmei Wang,
  • Wenjie Gong,
  • Wenjie Gong,
  • Tim Sauer,
  • Leopold Sellner,
  • Leopold Sellner,
  • Maria-Luisa Schubert,
  • Angela Hückelhoven-Krauss,
  • Jian Hong,
  • Lixin Zhu,
  • Christian Kleist,
  • Volker Eckstein,
  • Carsten Müller-Tidow,
  • Carsten Müller-Tidow,
  • Peter Dreger,
  • Peter Dreger,
  • Michael Schmitt,
  • Michael Schmitt,
  • Anita Schmitt

DOI
https://doi.org/10.3389/fimmu.2020.608167
Journal volume & issue
Vol. 11

Abstract

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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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