According to a new study, a novel T cell genetically engineered by scientists from The University of Arizona Health Sciences can target and attack pathogenic T cells that are responsible for causing Type 1 diabetes. These latest findings may result in new immunotherapy therapies.
The immune system uses many types of T cells to combat viruses, bacteria, and other pathogens. All these T cells have receptors that are specific to certain antigens. The receptor works on the killer T cells along with a coreceptor and three signaling modules to kill the infected cell.
Michael Kuhns, Ph.D., an associate professor from the College of Medicine -Tucson Department of Immunobiology at The University of Arizona, copied the evolutionary plan to design a five-module chimeric antigen receptor (5MCAR) T cell.
The 5MCAR was an attempt to figure out if we could build something by biomimicry, using some of evolution’s natural pieces, and redirect T cells to do what we want them to do. We engineered a 5MCAR that would direct killer T cells to target autoimmune T cells that mediate Type 1 diabetes.”
Michael Kuhns, PhD, Associate Professor, The University of Arizona College of Medicine
Dr. Kuhns is also a member of the Cancer Center at The University of Arizona, BIO5 Institute, and Arizona Center on Aging.
Dr. Kuhns continued, “So now, a killer T cell will actually recognize another T cell. We flipped T cell-mediated immunity on its head.”
Dr. Kuhns teamed up with Thomas Serwold, Ph.D., from the Harvard Medical School-affiliated Joslin Diabetes Center, to verify the 5MCAR T cells in a non-obese diabetic mouse model with potential outcomes. The new findings were recently published in the Proceedings of the National Academy of Sciences.
When we saw that the 5MCAR T cells completely eliminated the harmful T cells that invaded the pancreas, we were blown away. It was like they hunted them down. That ability is why we think that 5MCAR T cells have tremendous potential for treating diseases like Type 1 diabetes.”
Thomas Serwold, PhD, Joslin Diabetes Center, Harvard Medical School
Earlier in 2017, the U.S. Food and Drug Administration had approved a couple of chimeric antigen receptor (CAR) T cell therapies for certain types of cancer—one for treating children with acute lymphoblastic leukemia, and the other for treating adults with advanced lymphomas. These CAR T cells only targeted the receptor, and not the coreceptor or the surrounding signaling modules.
According to Dr. Kuhns, simulation of the form and function of a natural T cell, along with its complex five-module structure, could enable researchers to more particularly target antigens with higher sensitivity in the future. Personalized immunotherapy of this kind is a crucial step taken by The University of Arizona Health Sciences, as well as a research target for Dr. Kuhns’ laboratory.
I’m generally of the belief that evolution converges on related principles to execute related tasks. Basic research from labs around the world, including ours, has helped us to understand the complex structure and function of the five-module molecular machines that have evolved to drive T cell responses. We think these results show that a biomimetic approach holds promise for CAR engineering.”
Michael Kuhns, PhD, Associate Professor, University of Arizona College of Medicine
The National Institute of Allergy and Infectious Diseases recently awarded a bridge grant to Drs Kuhns and Serwold to continue their study into employing 5MCAR T cells to prevent autoimmune disease.
“There are many things we don't yet know about this technology. What we know is that it works, and it can be very effective in a mouse model of Type 1 diabetes, so that’s great. Now, we have a lot more work to do,” Dr Kuhns concluded.
Engineering 5MCAR T Cells to Target Pathogenic T Cells
Video Credit: University of Arizona Health Sciences.
Kobayashi, S., et al. (2020) A biomimetic five-module chimeric antigen receptor (5MCAR) designed to target and eliminate antigen-specific T cells. Proceedings of National Academy of Sciences. doi.org/10.1073/pnas.2012495117.