New York, NY – MSK multiple myeloma specialist Sham Mailankody, MBBS has led trials showing that CAR T cell therapy targeting an antigen called GPRC5D appears to be safe and effective against the disease. Results published in the New England Journal of Medicine in September 2022 showed that 71% of patients responded to the GPRC5D-directed immunotherapy, meaning their multiple myeloma shrank or disappeared, although some had significant side effects. Among 12 patients who received a lower dose with manageable side effects, the response rate was 58%.
Despite the promising responses, relapses are still common. Dr. Mailankody collaborated with leukemia specialist Omar Abdel Wahab, MD to understand the relapse mechanisms. They studied tumor samples from six relapsed patients to look for clues. In one patient, the team found evidence of biallelic deletion (loss of both copies of the GPRC5D gene) leading to a complete loss of the GPRC5D antigen. In the other five patients, they saw decreased or loss of expression of GPRC5D — although the reason for this was unclear. The finding suggests that genetic alterations may be an important mechanism of antigen escape — a way to evade immune recognition and response — after GPRC5D-directed CAR T-cell therapy. The research was led by first author hematologic oncology fellow Xiaoli Mi, MD.
To overcome antigen escape, Dr. Mailankody is now leading a clinical trial for patients with relapsed or resistant multiple myeloma by using a simultaneous infusion of CAR T cells targeting GPRC5D as well as BCMA, a protein on the surface of the CAR T cells.
“Our goal is to better understand mechanisms of resistance to these therapies and quickly translate these findings guide new, effective treatments for patients,” Dr. Mailankody says.
Contact
Ian Demsky
Memorial Sloan Kettering Cancer Center
[email protected]