At the 66th American Society of Hematology (ASH) Annual Meeting held in San Diego, a groundbreaking study from Roswell Park Comprehensive Cancer Center offered compelling new insights into how Venetoclax may enhance immune responses when combined with CAR T-cell therapy for patients with chronic lymphocytic leukaemia (CLL) — the most prevalent form of leukemia in the United States.
Led by Dr. Matthew Cortese, MD, MPH, Assistant Professor of Oncology in Roswell Park’s departments of Medicine and Cancer Genetics & Genomics, the research uncovers an additional, previously underappreciated benefit of Venetoclax: its ability to fortify the cancer-fighting capabilities of T lymphocytes. While Venetoclax has been an FDA-approved therapy for CLL since 2019, primarily known for inducing apoptosis in malignant B cells by targeting the BCL-2 protein, this study reveals that its therapeutic reach may extend beyond cytotoxicity — into the realm of immune modulation.
CLL is characterized by the unchecked proliferation of dysfunctional B cells, which not only drive disease progression but also impair immune function, leading to vulnerability to infections and resistance to treatments, including CAR T-cell therapies. Dr. Cortese’s findings suggest that Venetoclax, when integrated into a therapeutic regimen alongside CAR T-cell therapy, may help overcome some of these barriers by enhancing the vitality and function of T cells.
To explore this synergistic interaction, researchers collected peripheral blood samples from 14 CLL patients undergoing standard-of-care Venetoclax therapy. Using a comprehensive, multiomic approach — incorporating RNA sequencing, flow cytometry, epigenomics, and metabolomics — the team assessed immune cell changes pre- and post-treatment. This layered molecular analysis was processed through advanced bioinformatic pipelines, offering a high-resolution view of how Venetoclax reshapes the immune landscape.
The most revealing aspect of the study came when CAR T cells were generated from patient samples taken before and after Venetoclax treatment. These engineered cells were then tested in vitro against aggressive lymphoma models. Results showed that post-Venetoclax CAR T cells displayed improved cytotoxic performance, underscoring the drug’s capacity to prime T cells for enhanced therapeutic efficacy.
Dr. Cortese emphasized that this evolving understanding of Venetoclax positions it not only as a direct anti-leukemic agent but also as a potential immunomodulatory enhancer in combination therapies. As Roswell Park prepares for future clinical trials to build on this data, the goal is to harness Venetoclax’s full potential in precision oncology — developing more durable, less toxic treatments that could edge closer to a cure.
Senior author Dr. Francisco Hernandez-Ilizaliturri, Professor of Oncology and Director of Lymphoma Research, highlighted that such synergistic strategies may redefine standards of care in CLL. As the field continues to pursue ultra-personalized medicine, Venetoclax stands out as a cornerstone compound in efforts to integrate targeted and cellular therapies for transformative patient outcomes.
Reference: https://ecancer.org/en/news/25779-ash-2024-study-reveals-how-venetoclax-boosts-immune-response-to-car-t-for-chronic-lymphocytic-leukaemia
