Blocking a specific protein improves CAR T-cell therapy success in patients with blood cancers

University of Maryland School of Medicine (UMSOM) Researchers have identified a target that may improve the response of CAR T-cell therapy, a treatment for patients with recurrent or difficult to treat blood cancers.

In a recent study published in Signal Transduction and Targeted Therapy, scientists found increased survival and tumor-fighting activity in lab and animal models when they blocked a specific protein in the modified cells.

CAR T-cell therapy involves genetically engineering a patient's T-cells, or immune cells, to attack cancer cells and then infusing those cells back into the patient. The therapy can be remarkably effective, but most patients still experience a relapse within 5 years of treatment.

Genetically engineered cells are a promising new way to treat cancer and autoimmune diseases. However, scientists are still figuring out how these cells work and how to make them better."

Tim Luetkens, MD, Associate Professor of Microbiology and Immunology at UMSOM and senior author of the study

Kenneth Dietze, PhD, first author of this study and a research fellow in the Luetkens lab at UMSOM, discovered that some CAR T-cells tear off tiny pieces from the surface of cancer cells and put those pieces onto themselves. "This process makes the CAR T-cells less effective at attacking cancer," said Dr. Luetkens, who is also Director of Research and Development at the University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center (UMGCCC) Fannie Angelos Cellular Therapeutics GMP Lab.

This is a lattice light sheet microscopy image of a CAR T cell (purple cell in the middle), ripping fragments off the surrounding tumor cells (green cells). The image was created by Kiet Nguyen, Elizabeth Anne Kiely, and Dr. Arpita Upadhyaya.

The study team discovered that blocking a protein called cathepsin b prevented the tearing process in CAR T-cells and allowed them to stay active longer, therefore making them better at fighting cancer.

"I am proud of UMGCCC's continued innovation in CAR T-therapy," said Taofeek K. Owonikoko, MD, PhD, Executive Director of UMGCCC and the Kevin Cullen Distinguished Professor in Oncology at UMSOM. "While these findings need to be translated into human clinical trials, this is real progress that could ultimately improve durability and outcomes for our patients."

UMGCCC researchers are also leading an ongoing first-in-human clinical trial using CAR T-cell therapy in patients with recurrent or difficult-to-treat B-cell lymphoma. 

This research was done together with the Upadhyaya lab at the University of Maryland, College Park, where the team used advanced imaging techniques to directly watch how CAR T-cells tear off fragments from cancer cells.

This work was supported through the Maryland Department of Health's Cigarette Restitution Fund Program (CH-649-CRF), the National Cancer Institute Cancer Center Support Grant (P30CA134274), the National Cancer Institute of the National Institutes of Health (1R21CA297125), the National Institutes of Health (R35 GM145313), an NIAID-funded predoctoral fellowship (T32 AI095190), and the American Cancer Society (DBG-25-1434942-01-ET)."