Expanding CAR T Cells Using Venetoclax For Enhanced Cytolytic Activity Against Tumors

SUMMARY

Expanding CAR T cells with venetoclax enhances their ability to target and kill CD19+ tumor cells, increases their effectiveness, and reduces exhaustion, potentially leading to better treatment outcomes for diffuse large B cell lymphoma.

The Unmet Need: Methods to increase CAR T efficacy and reduce exhaustion

• Antigen Receptor T-cells (CAR T cells) have revolutionized the field of immunotherapy, showing significant promise in treating certain types of blood cancers, such as diffuse large B-cell lymphoma (DLBCL). These engineered T-cells are designed to target and kill cancer cells more effectively than conventional treatments. Despite their effectiveness, a substantial need exists for improving the persistence and cytotoxic capabilities of CAR T cells to enhance patient outcomes. This has led to a surge in research focusing on genetic and drug-based modifications to sustain the anti-tumor activity of CAR T cells.
• Current approaches to enhancing CAR T cell efficacy, although promising, face significant challenges. One major issue is the potential for T-cell exhaustion, a state where T-cells lose their ability to function effectively, which compromises their long-term efficacy. Additionally, existing strategies do not adequately address the intrinsic apoptotic pathways, which play a critical role in the regulation of immune cell survival and function. Without targeted intervention in these pathways, enhancing CAR T cell function remains limited, making it imperative to explore novel strategies to overcome these barriers, improve the genetic landscape, and optimize the anti-tumor efficacy of CAR T cells in clinical settings.

The Proposed Solution: Novel combination therapy with venetoclax amplifying CAR T-cell antigen-specific antitumor activity and prolonged function

• The faculty inventor developed methods to expand human anti-CD19 CAR T cells using venetoclax, a small-molecule BCL-2-specific BH3 mimetic. This expansion results in enhanced antigen-specific cytolytic capabilities of CAR T cells in vitro and increased effectiveness against CD19+ diffuse large B cell lymphoma (DLBCL) in pre-clinical animal models. Additionally, treatment with venetoclax alters the genetic landscape of the CAR T cells, increasing both BCL-2 protein and mRNA expression, which is suggestive of reduced cell exhaustion and modified metabolism. Importantly, the cytolytic effects are observed in CAR T cells using costimulatory domains, which are commonly employed in commercial CAR T cell therapies.
• This approach leverages the intrinsic apoptotic pathway to amplify CAR T cell efficacy, a novel approach not previously explored. The introduction of drug-based interventions like venetoclax to modulate BCL-2 expression presents a significant improvement over existing CAR T cell therapies, as it directly addresses T cell exhaustion and metabolic changes, potentially resulting in superior patient outcomes for those with CD19+ lymphomas.

ADVANTAGES

ADVANTAGES

• Increased antigen-specific cytolytic capabilities of CAR T cells

• Increased BCL-2 protein and mRNA expression in CAR T cells

• Decreased exhaustion and altered metabolism

• Effective with costimulatory domains

APPLICATIONS

• CAR T cell therapy
• Cancer immunotherapies
• Drug-enhanced cell therapy

• Enhanced effectiveness against human CD19+ diffuse large B cell lymphoma (DLBCL) in pre-clinical animal models