Dr Hernandez-Ilizaliturri on Immunologic Changes in Venetoclax-Treated CLL

“BCL-2 inhibition with venetoclax could be… used to further enhance the T-cell function of patients, and it can potentially be used to enhance CAR T-cell therapy options, or other T-cell engaging options, for patients with CLL and perhaps other types of lymphomas.”

Francisco J. Hernandez-Ilizaliturri, MD, professor, oncology, Department of Medicine – Lymphoma, director, Lymphoma Research, head, Lymphoma Translational Research Lab, associate professor, Department of Immunology, Roswell Park Comprehensive Cancer Center; clinical professor, Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, discusses findings from a multiomic study investigating immunologic changes in patients with chronic lymphocytic leukemia (CLL) who received treatment with venetoclax (Venclexta).

This study found that patients with CLL exhibit T-cell exhaustion, characterized by impaired T-cell function, which likely contributes to their susceptibility to infections and secondary cancers, Hernandez-Ilizaliturri begins. This study showed that treatment with venetoclax, a BCL-2 inhibitor, improved T-cell fitness within 1 month of therapy initiation. This improvement included metabolic reprogramming, where T cells shift to using lipids for energy production—a process associated with enhanced immune responses, he explains.

Additionally, treatment with venetoclax was shown to induce surface changes on T cells, priming them for improved cytotoxic activity against infectious agents and potentially against cancer cells as well, Hernandez-Ilizaliturri notes. A killing assay using standard cell lines showed that T cells that were engineered into CAR T cells after 1 month of venetoclax exposure demonstrated significantly enhanced in vitro lymphoma cell killing efficiency compared with untreated T cells.

These findings indicate that BCL-2 inhibition with venetoclax targets malignant cells and rejuvenates the immune system by enhancing T-cell function, Hernandez-Ilizaliturri emphasizes. This dual mechanism of action positions venetoclax as a potential adjunctive therapy that may improve outcomes with CAR T-cell therapy or other T-cell–engineered immunotherapies in patients with CLL and other lymphomas, he concludes.