Research out of Roswell Park Comprehensive Cancer Center has shed light on how the drug venetoclax works synergistically with CAR T-cell immunotherapy to combat chronic lymphocytic leukaemia (CLL), the most common type of leukaemia in the U.S. 

Matthew Cortese, MD, MPH, Assistant Professor of Oncology in Roswell Park’s departments of Medicine and Cancer Genetics & Genomics, is first author of the study, which he presented during an oral abstract session at the 66th annual meeting of the American Society of Hematology (ASH) in San Diego, California.

Chronic lymphocytic leukaemia occurs when B cells — infection-fighting white blood cells that are part of the immune system — grow out of control, suppressing the immune system. This can lead to additional cancers, frequent infections and resistance to treatments such as CAR T-cell therapy.

Matthew Cortese, MD, MPH, Assistant Professor of Oncology in Roswell Park’s departments of Medicine and Cancer Genetics & Genomics

FDA-approved for the treatment of CLL since 2019, venetoclax can cause CLL cells to self-destruct by inhibiting BCL-2, a protein they need to survive.

But the Roswell Park study reveals that when it is combined with CAR T-cell therapy, venetoclax works in another way that’s less understood — by strengthening cancer-killing T lymphocytes, or T cells, improving their function and fitness.

“This could be an exciting way to repair the immune system in patients with CLL,” says Dr. Cortese, who notes that Roswell Park is working to develop a clinical trial that would take the next step in this discovery.

To better understand the drug’s effects on the immune system, the research team collected circulating blood from 14 Roswell Park patients whose treatment plan began with standard-of-care venetoclax to treat their CLL.

Using specialised facilities and a multidisciplinary approach at Roswell Park, the team compared those initial blood samples with samples taken after about 30 days of venetoclax treatment, to identify specific changes in patients’ immune cells.

This “multiomic” analysis included RNA sequencing, flow cytometry, epigenomics and metabolomics.

Data from each layer were combined with sophisticated bioinformatic analytical tools. CAR T cells were then made from baseline and treated blood samples and tested against aggressive lymphoma cell lines in the lab.

“By analysing 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,” says 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.”

Francisco Hernandez-Ilizaliturri, MD, Professor of Oncology and Director of Lymphoma Research in the Department of Medicine and Associate Professor in the Department of Immunology, is senior author of the study.

Source: Roswell Park Comprehensive Cancer Center