Comparative analysis of Bcl-2 family protein overexpression in CAR T cells alone and in combination with BH3 mimetics.

in Science translational medicine by Felix Korell, Michael L Olson, Diego Salas-Benito, Mark B Leick, Rebecca C Larson, Amanda Bouffard, Harrison Silva, Alessandro Gasparetto, Trisha R Berger, Michael C Kann, Markus Mergen, Tamina Kienka, Marc Wehrli, Nicholas J Haradhvala, Stefanie R Bailey, Anthony Letai, Marcela V Maus

TLDR

  • The study found that CAR T cells can be made more effective at fighting cancer by overexpressing a protein called Bcl-xL. This protein helps the CAR T cells survive longer and be more effective at killing cancer cells. The study also found that combining Bcl-xL overexpression with a drug called venetoclax can make the CAR T cells even more effective at killing cancer cells. The study suggests that CAR T cells could be made even more effective by overexpressing Bcl-xL and using venetoclax together.

Abstract

Approximately 50% of patients with hematologic malignancies relapse after chimeric antigen receptor (CAR) T cell treatment; mechanisms of failure include loss of CAR T persistence and tumor resistance to apoptosis. We hypothesized that both of these challenges could potentially be overcome by overexpressing one or more of the Bcl-2 family proteins in CAR T cells to reduce their susceptibility to apoptosis, both alone and in the presence of BH3 mimetics, which can be used to activate apoptotic machinery in malignant cells. We comprehensively investigated overexpression of different Bcl-2 family proteins in CAR T cells with different signaling domains as well as in different tumor types. We found that Bcl-xL and Bcl-2 overexpression in CAR T cells bearing a 4-1BB costimulatory domain resulted in increased expansion and antitumor activity, reduced exhaustion, and decreased apoptotic priming. In addition, CAR T cells expressing either Bcl-xL or a venetoclax-resistant Bcl-2 variant led to enhanced antitumor efficacy and survival in murine xenograft models of lymphoma and leukemia in the presence or absence of the BH3 mimetic venetoclax, a clinically approved BH3 mimetic. In this setting, Bcl-xL overexpression had stronger effects than overexpression of Bcl-2 or the Bcl-2(G101V) variant. These findings suggest that CAR T cells could be optimally engineered by overexpressing Bcl-xL to enhance their persistence while opening a therapeutic window for combination with BH3 mimetics to prime tumors for apoptosis.

Overview

  • The study investigates the use of chimeric antigen receptor (CAR) T cells in the treatment of hematologic malignancies. The hypothesis is that overexpressing one or more of the Bcl-2 family proteins in CAR T cells can reduce their susceptibility to apoptosis and improve their antitumor activity. The study uses different signaling domains and tumor types to investigate the effects of Bcl-xL and Bcl-2 overexpression on CAR T cell expansion, antitumor activity, exhaustion, and apoptotic priming. The study also investigates the effects of Bcl-xL and Bcl-2 overexpression on CAR T cell survival in the presence or absence of the BH3 mimetic venetoclax.

Comparative Analysis & Findings

  • The study found that overexpression of Bcl-xL and Bcl-2 in CAR T cells bearing a 4-1BB costimulatory domain resulted in increased expansion and antitumor activity, reduced exhaustion, and decreased apoptotic priming. In addition, CAR T cells expressing either Bcl-xL or a venetoclax-resistant Bcl-2 variant led to enhanced antitumor efficacy and survival in murine xenograft models of lymphoma and leukemia in the presence or absence of the BH3 mimetic venetoclax. The study also found that Bcl-xL overexpression had stronger effects than overexpression of Bcl-2 or the Bcl-2(G101V) variant.

Implications and Future Directions

  • The study's findings suggest that CAR T cells could be optimally engineered by overexpressing Bcl-xL to enhance their persistence while opening a therapeutic window for combination with BH3 mimetics to prime tumors for apoptosis. The study identifies Bcl-xL as the most effective protein for enhancing CAR T cell survival and antitumor activity. The study also identifies the need for further research to investigate the effects of Bcl-xL overexpression on CAR T cell survival and antitumor activity in clinical trials. The study also identifies the need for further research to investigate the effects of Bcl-xL overexpression on CAR T cell exhaustion and apoptotic priming.
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