Roswell Park Comprehensive Cancer Center researchers have uncovered how venetoclax (Venclexta) enhances the effectiveness of CAR T-cell immunotherapy in treating chronic lymphocytic leukemia (CLL). The study, presented at the 66th annual meeting of the American Society of Hematology (ASH), reveals that venetoclax strengthens cancer-killing T lymphocytes, improving their function and fitness when combined with CAR T-cell therapy.
Venetoclax's Synergistic Effect
Chronic lymphocytic leukemia, the most common type of leukemia in the U.S., occurs when B cells grow uncontrollably, suppressing the immune system. Venetoclax, FDA-approved for CLL treatment since 2019, induces CLL cell self-destruction by inhibiting BCL-2. The new research demonstrates that venetoclax also bolsters the immune system by enhancing T cell function.
"This could be an exciting way to repair the immune system in patients with CLL," said Dr. Matthew Cortese, Assistant Professor of Oncology at Roswell Park and first author of the study. Roswell Park is planning a clinical trial to further explore these findings.
Multiomic Analysis
To understand venetoclax's impact on the immune system, the research team collected blood samples from 14 CLL patients before and after 30 days of venetoclax treatment. Using multiomic analysis, including RNA sequencing, flow cytometry, epigenomics, and metabolomics, the team identified specific changes in the patients’ immune cells. CAR T cells were then created from these samples and tested against aggressive lymphoma cell lines in the lab.
Implications for Treatment
The study's senior author, Dr. Francisco Hernandez-Ilizaliturri, Professor of Oncology and Director of Lymphoma Research, emphasized the potential for developing more effective combination treatments for CLL patients. "By analyzing very large volumes of molecular data in more patients, we hope to develop more effective combination treatments for CLL patients that improve on our best current treatments," said Dr. Cortese. "It’s hyper-precision medicine. The goal is to reduce side effects while bringing about ultra-deep responses by combining targeted therapies with immune and cellular therapies, which down the road may ultimately lead to a cure for some patients."
Venetoclax Improves CAR T-cell Function in Resistant B-cell Lymphomas
In a separate study, researchers at Roswell Park Comprehensive Cancer Center found that adding venetoclax to standard treatment may improve outcomes in patients with treatment-resistant B-cell lymphomas, including diffuse large B cell lymphoma (DLBCL). The team, led by Francisco Hernandez-Ilizaliturri, MD, used RNA sequencing to investigate whether venetoclax could improve the quality and function of T cells generated by adoptive cell therapies such as anti-CD19 CAR T-cell therapy.
The study revealed 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 posit that venetoclax induces T cell-intrinsic changes via calcium signaling modulation.
"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."
