Researchers at the University of Maryland School of Medicine (UMSOM) have identified a protein target that, when blocked, may improve the efficacy and durability of CAR T-cell therapy for blood cancers. The findings, based on laboratory and animal models, were published in the journal Signal Transduction and Targeted Therapy.
Key Findings
The study focused on the protein cathepsin B. Researchers found that blocking cathepsin B in CAR T-cells prevented the cells from tearing fragments off cancer cells and incorporating those fragments onto their own surface.
According to the researchers, this incorporation process had been reducing the effectiveness of the CAR T-cells.
- Mechanism: CAR T-cells were observed tearing fragments from cancer cells and incorporating them, which diminished their anti-tumor activity.
- Intervention: Blocking the protein cathepsin B prevented this tearing process.
- Outcome: In laboratory and animal models, the modification resulted in increased survival of the CAR T-cells and maintained their tumor-fighting activity for a longer period.
Background on CAR T-Cell Therapy
CAR T-cell therapy involves genetically engineering a patient's own T-cells to recognize and attack cancer cells. The modified cells are then reinfused into the patient. While the therapy has shown initial effectiveness, data indicates that many patients relapse within five years of treatment.
Research Methods
Advanced imaging techniques, specifically lattice light sheet microscopy, were used to directly observe the process of CAR T-cells tearing cancer cell fragments. This imaging was performed in collaboration with the Upadhyaya lab at the University of Maryland, College Park.
Statements from Researchers
- Tim Luetkens, MD, Associate Professor at UMSOM and senior author of the study, said: "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."
- Kenneth Dietze, PhD, a research fellow at UMSOM and first author of the study, discovered the process of fragment-tearing by CAR T-cells.
- Taofeek K. Owonikoko, MD, PhD, Executive Director of the University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center (UMGCCC), said: "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."
Ongoing and Future Research
Researchers noted that the findings require translation into human clinical trials. Currently, UMGCCC is conducting a first-in-human clinical trial using CAR T-cell therapy for recurrent or difficult-to-treat B-cell lymphoma.
Funding
The study was supported by the Maryland Department of Health’s Cigarette Restitution Fund Program, the National Cancer Institute Cancer Center Support Grant, the National Institutes of Health, the NIAID predoctoral fellowship, and the American Cancer Society.
About UMGCCC
The University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center (UMGCCC) is an NCI-designated comprehensive cancer center. It provides multidisciplinary cancer care and conducts clinical and basic science research. The center is ranked among the top 50 cancer programs in the United States by US News & World Report.