TAMPA, Fla. (Nov. 13, 2020) Chimeric antigen receptor T-cell therapy, or 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. CAR T cells can produce strong response rates; however, many patients develop resistance and relapse because of poor CAR T-cell activity and survival. Moffitt Cancer Center researchers are working to improve CAR T responses and make those responses more long-lasting for patients. 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 enhances 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, Ph.D., 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.

This study was supported by the National Cancer Institute (P30-CA076292) and Atara Biotherapeutics.

About Moffitt Cancer Center
Moffitt is dedicated to one lifesaving mission: to contribute to the prevention and cure of cancer. The Tampa-based facility is one of only 51 National Cancer Institute-designated Comprehensive Cancer Centers, a distinction that recognizes Moffitt’s scientific excellence, multidisciplinary research, and robust training and education. Moffitt is the No. 11 cancer hospital and has been nationally ranked by U.S. News & World Report since 1999. Moffitt’s expert nursing staff is recognized by the American Nurses Credentialing Center with Magnet® status, its highest distinction. With more than 7,000 team members, Moffitt has an economic impact in the state of $2.4 billion. For more information, call 1-888-MOFFITT (1-888-663-3488), visit MOFFITT.org, and follow the momentum on Facebook, Twitter, Instagram and YouTube