Cell-free DNA analysis of persistent CAR T-cell populations in humans
Mark HamiltonMD PhD
Project Term: July 1, 2022 - TBD
The focus of this research project is to understand how therapeutic chimeric antigen receptor (CAR) T-cells mediate long-term remission of diffuse large B-cell lymphomas. I will use cell free DNA collected from patient plasma to understand if there is an association of CAR T-cell persistence and long-term tumor remission. The goal of this research is to define how CAR T-cells suppress tumors over time to develop better CAR T-cells in the future.
Chimeric antigen receptor (CAR) T-cells are a new anti-cancer therapy that use cell engineering to “teach” the patient’s own immune systemic how to kill cancer. CAR T-cell therapy is currently revolutionizing the treatment of leukemia and lymphoma because of its ability to generate complete responses in patients who have cancers that are resistant to conventional treatments. Despite the remarkable ability of CAR T-cells to kill tumors, some treated tumors progress at later dates. The precise timing and mechanisms by which CAR T-cells kill tumors, and why the therapy sometimes fails, is still being studied.
I hypothesize that there is a population of persistent CAR T-cells that is important for suppressing tumor growth over long periods of time. This population of cells may be responsible for generating durable remissions and even cures in patients treated with CAR T-cells. Demonstrating that persistent CAR T-cell populations are responsible for long-term tumor suppression would be a major step in understanding how CAR T-cells function.
Diffuse large B-cell lymphoma is the most common lymphoma in humans and is very aggressive. This cancer is often cured with chemotherapy, but up to 50% of patients relapse and need further treatment. CAR T-cells are increasingly used to treat relapsed disease. In this project I will use cell-free DNA analysis of patients with diffuse large B-cell lymphoma to understand how CAR T-cells and tumors interact.
Cell-free DNA sequencing is a genomic technology that allows for highly sensitive detection of cellular DNA in human blood samples. Both CAR T-cells and tumors have unique DNA sequences that can be tracked in cell free DNA. With cell free DNA sequencing I can use stored blood samples from patients who have been treated with CAR T-cells to noninvasively track levels of both the CAR T-cell and the tumor over time to see if there is an association between persistence of the CAR T-cells and tumor suppression.
The result of this study will improve understanding of how CAR T-cells fundamentally work by defining a population of CAR T-cells that are critical to mediating durable tumor remissions. By understanding which subsets of CAR T-cells are important in generating durable remissions we can design new CAR T-cell treatments that prevent tumor recurrence.