BOSTON – (November 2, 2020) – T cells with a biomimetic-designed chimeric antigen receptor (CAR) can specifically target and eliminate pathogenic T cell populations, according to new research published in PNAS. Specifically, the researchers use the approach to demonstrate how type 1 diabetes in mice that is induced by such pathogenic T cells can effectively be prevented from developing in the first place.
As well as the clear implications for the disease, the authors suggest that with more work the approach is likely relevant to other autoimmune-related diseases including multiple sclerosis and some cancers as well as the protection of transplanted tissues.
The research, which was co-led by Thomas Serwold, PhD, of Joslin Diabetes Center and Michael S. Kuhns, PhD, of the University of Arizona College of Medicine in Tucson, was published online today by the Proceedings of the National Academy of Sciences (PNAS).
While CAR-T cell therapy has been in development for a while and has shown clinical success with some B cell lymphomas, the approach has suffered from a number of drawbacks including the dosing required, their specificity and their sensitivity.
To address such issues, the team tested a five-module chimeric antigen receptor or 5MCAR to emulate T cell responses that are naturally driven by five-module antigen receptors. The main aim of the design, which was engineered in the Kuhns Lab, was to redirect cytotoxic T cells with the 5MCAR to target and eliminate pathogenic T cells in the initial setting of type 1 diabetes.
In their evaluation of the 5MCAR T cells, the authors detail their design and initial in vitro characterization, reporting that the system can re-direct cytotoxic T cells to specifically kill CD4+ T cell targets in cell cultures.
After establishing their basic functionality, they found that the 5MCAR T cells could be directed to kill a specific pathogenic CD4+ T-cell known to mediate pancreatic β-cell destruction in a mouse model of diabetes.
Moving to in vivo studies with the mouse model, the authors then established that the 5MCAR T cells could rapidly find and eliminate the CD4+ T cell targets and prevent the development of diabetes in mice that received both the CAR-T cell treatment and pathogenic CD4+ T cells. In contrast, all untreated or control mice developed diabetes.
Further investigations revealed the extent of pancreatic damage in the control and untreated mice as compared to the treated mice. Longer-term experiments further established that the 5MCAR T cells could engraft for up to a year following administration, raising some hope for long-term protection.
Discussing the findings, the authors go into some detail on the thinking behind the design of the biomimetic CAR-T cells, their potential research applications (particularly in relation to studying immune responses) and their potential in therapeutic applications in diseases mediated by pathogenic T cells. For type 1 diabetes, the authors point out that there is a window of opportunity for prevention when it is known that an at-risk individual has two or more diabetes-related autoantibodies.
Commenting on the outcomes, Dr Michael S. Kuhns said:
“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. These insights motivated us to ask if we could engineer a biomimetic five-module CAR that mirrors the form and function of the natural counterpart. We think these results show that a biomimetic approach holds promise for CAR engineering.”
When we saw that our 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
Assistant Professor of Medicine, Harvard Medical School
Other contributors to the research include Shio Kobayashi, Martin A. Thelin, Heather L. Parish, Neha R. Dehpande, Mark S. Lee, Alborz Karimzadeh and Monica A. Niewczas. Funding was provided by The University of Arizona College of Medicine, the BIO5 Institute, the National Institutes of Health, the Pew Scholars Program, the University of Arizona Foundation, the Cancer Center Support Grant, the Fleisher Family Foundation, the Alexander and Margaret Stewart Trust, the Iacocca Family Foundation, the Swedish Society of Medicine, the Swedish Society of Medical Research, Harvard Catalyst, and the Harvard Clinical and Translational Science Center.
Corresponding authors: Dr Thomas Serwold (thomas.serwold [at] joslin.harvard.edu) and Dr Michael S. Kuhns (mkuhns [at] arizona.email.edu
Reference: Kobayashi and Thelin et al. A biomimetic chimeric antigen receptor (5MCAR) designed to target and eliminate antigen-specific T cells.