Can Venetoclax Boost Response to CAR T-Cell Therapy in CLL?

By: Vanessa A. Carter, BS
Posted: Tuesday, January 21, 2025

Matthew J. Cortese, MD, MPH, of Roswell Park Comprehensive Cancer Center, Buffalo, New York, and colleagues evaluated the use of venetoclax in patients with chronic lymphocytic leukemia (CLL). The results of this study, which were presented during the 2024 American Society of Hematology (ASH) Annual Meeting & Exposition (Abstract 78), suggest that not only does venetoclax enhance T-cell function, but it also seems to amplify chimeric antigen receptor (CAR) T-cell cytotoxicity in this patient population.

“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 in a Roswell Park press release “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.”

Clinicopathologic data and peripheral blood samples were collected from 13 patients with CLL at baseline and after venetoclax ramp-up, which occurred 30 days after treatment. Machine learning and bioinformatics tools were used to conduct comparative multiomic analysis, and CAR T cells were synthesized at baseline and day 30.

Of 12 patients with bulky disease, all were successfully debulked prior to day 30. Flow cytometry performed 30 days after treatment demonstrated an increase in CD8-positive T-cell frequency, CD8-positive T-stem cell memory, and T-naive memory subsets. There appeared to be a significant upregulation of genes crucial for the development, activation, and survival of CD8-positive and CD4-positive memory T cells.

RNA sequencing conducted after treatment identified a significant upregulation in differentially expressed genes related to M1 macrophage polarization, neutrophil migration and chemoattraction, T-cell inflammatory cytokine production and cytotoxic function, and monocyte/macrophage differentiation markers. It was noted that better responders had 1,698 positive differentially expressed genes associated with cytokine signaling and T-cell activation.

Disclosure: For full disclosures of the study authors, visit ash.confex.com.

2024 ASH Annual Meeting & Exposition