Chimeric antigen receptor T-cell therapy, or CAR T, can produce strong response rates; however, many patients develop resistance and relapse because of poor CAR T-cell activity and survival. That is why researchers at Moffitt Cancer Center are working to improve CAR T responses and make those responses more long-lasting for patients, according to a press release.
CAR T is a type of cellular immunotherapy approved to treat several hematologic malignancies, including B cell acute lymphoblastic leukemia and aggressive B cell lymphomas. In a new article published in Cancer Immunology Research, the team shares its findings, which show alterations to a specific domain of the chimeric antigen receptor enhance CAR T-cell activity and survival.
In CAR T-cell therapy, a patient’s own T cells are harvested and genetically engineered to target a biomarker found on cancer cells. The CAR T cells are then infused back into the patient. Ideally, the engineered T cells should further reproduce within the patient and seek out the cancer cell biomarker to attack.
“While CAR T cells have shown promising activity in different cancer types, they also have several limitations including the development of T cell exhaustion, during which the engineered T cells progressively stop functioning,” said Marco Davila, M.D., Ph.D., medical director of Cell Therapies and associate member of the Department of Blood & Marrow Transplant and Cellular Immunotherapy at Moffitt.
While some scientists believe that T cell exhaustion is solely due to the quantity of the T cell signal, Davila’s team believes that quality of T cell signaling also contributes to exhaustion. First generation CAR T cells include an activation domain of the T cell called CD3z. However, in order to produce a better immune reaction, newer generations of CAR included a second or third costimulatory domain, such as CD28 or 4-1BB.
The Moffitt researchers wanted to determine if alterations of the CD28 costimulatory domain could impact CAR T-cell exhaustion and enhance their persistence and activity. They created CARs that retained only one out of three known functional subdomains of CD28 and tested the T cells’ ability to promote survival in mice with B cell acute lymphoblastic leukemia. CAR T cells that contained only the PYAP subdomain allowed 100% of the mice to survive up to 62 days, while only half of mice treated with the normal CAR T cells survived during the same period. Importantly, T cells modified with a CAR that retained either of the remaining subdomains, YMNM or PRRP, did not support the same enhanced function showing reduction of signaling alone does not prevent T cell exhaustion.
The team analyzed how the mutant CAR T cells were able to produce this survival benefit. They observed that the PYAP-only CAR T cells were more sensitive to the presence of the tumor marker. They also discovered that the PYAP-only CAR T cells were less likely to turn on genes that are associated with exhaustion than standard second-generation CARs.
“Our work demonstrates that the function of second-generation CAR T cells can be optimized by modulating the CD28 costimulatory domain. We found that the PYAP-only CAR T cells had reduced levels of the genes NFAT, NUR77 and PD1, which are all known to contribute to T cell exhaustion,” said Justin Boucher, PhD, lead study author and postdoctoral fellow at Moffitt.
Boucher added additional research is needed to see if drugs targeting NFAT and/or NUR77 signaling pathways can be used to strengthen CAR T patient response and durability.
