About a third of patients with diffuse large B cell lymphoma (DLBCL), a fast-growing form of lymphoma, will see their disease advance or recur following treatment. Seeking a new treatment strategy that might boost the effectiveness of existing DLBCL therapies, a team from Roswell Park Comprehensive Cancer Center has been working to understand the underlying mechanisms of the targeted chemotherapy venetoclax. Their findings, to be presented during a talk today at the 66th annual meeting of the American Society of Hematology (ASH) in San Diego, California, provide strong preclinical evidence that adding venetoclax to standard treatment may improve outcomes in patients with treatment-resistant B-cell lymphomas.

For the new study, a team led by Francisco Hernandez-Ilizaliturri, MD, Professor of Oncology and Director of Lymphoma Research in Roswell Park’s Department of Medicine, used RNA sequencing to investigate whether venetoclax (brand name Venclexta), FDA-approved to treat some leukemias, could improve the quality and function of T cells generated by adoptive cell therapies such as anti-CD19 CAR T (chimeric antigen receptor T-cell) therapy.

The team set out to validate findings from their earlier work documenting venetoclax-induced changes within CAR T cells — specifically, increased population frequency of the desirable T stem cell memory subset, increased cytotoxicity to laboratory-generated relapsed/refractory lymphoma cells, and increased population frequency of CD8+ cytotoxic effector cells.

Analyzing results from transcriptomic sequencing of T cells from three healthy donors, in the new data being presented today, the team reveals previously unknown fundamental characteristics of CAR T cell and T cell biology, elucidating the mechanism behind venetoclax’s desirable impacts on T cell quality and function.

“Because it inhibits the Bcl-2 proteins associated with poor response to existing therapies for B-cell lymphomas, we expected that venetoclax would have a direct impact on CAR T cell populations through mitochondrial or endoplasmic reticulum (ER) protein interaction and localization,” says presenting author Taylor Mandeville, a doctoral candidate in Dr. Hernandez-Ilizaliturri’s lab. “Using RNA sequencing, we have successfully identified how venetoclax influences the phenotypic and qualitative changes in CAR T cells observed in prior preclinical studies.”

“Our data suggest that Venetoclax induced significant changes in CAR T cell function related to cytotoxicity (IFNG, GZMB), activation and survival (CD69, IL2), memory and immunomodulation (TCF7, IL12RB2, FOXP3), Bcl-2 family expression (BCL2, MCL1), and mitochondrial function,” the authors write. “We posit that venetoclax induces T cell-intrinsic changes via calcium signaling modulation.”

DLBCL is the most common type of non-Hodgkin lymphoma, affecting more than 18,000 people newly diagnosed with this aggressive form of cancer each year in the United States.

“Our goal is to transcend the current limitations of CAR T therapy for the treatment of lymphoma,” says Dr. Hernandez-Ilizaliturri. “While further studies clarifying the effect of venetoclax exposure on CAR T-cell function are needed, our findings present a strong rationale for advancing this strategy toward an early-stage clinical trial.”

Source – Roswell Park Comprehensive Cancer Center