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.”
Presentation details
For more information about Roswell Park presenting doctors and ASH conference activities, please visit https://www.roswellpark.org/ASH. To arrange interviews with the Roswell Park team, contact Julia Telford at [email protected].
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SOURCE Roswell Park Comprehensive Cancer Center
