# Engineering 2nd generation 5MCARs to monitor and treat Type-I Diabetes

> **NIH NIH R01** · UNIVERSITY OF ARIZONA · 2024 · $828,648

## Abstract

PROJECT SUMMARY
This proposal is aimed at developing immune cell engineering approaches for the monitoring and treatment of
T cell-mediated autoimmune diseases such as Type-I diabetes (T1D). The native 5-module receptor
complexes that drive T cell responses to peptide antigens embedded in MHC molecules have evolved through
an iterative process over the last ~435 million years to optimize T cell responses to a broad range of
challenges. Using a biomimetic approach, we have developed a 5-module chimeric antigen receptor (5MCAR)
and reported that cytotoxic T cells expressing 5MCARs (5MCAR-CTLs) can specifically target and kill
autoimmune CD4+ T cells that mediate T1D in preclinical mouse models, resulting in significantly reduced
disease incidence in 5MCAR-CTL-treated mice. Our proof-of-concept work supports the idea, echoed by the
RFA to which we are responding, that engineered immune cell-based immunotherapies hold promise for the
treatment of autoimmune diseases. Also as noted in the RFA, this area of investigation is in its infancy and
requires support of exploratory engineering approaches to reach its full potential. Our foundational work
provides us with a novel platform from which to continue the development of novel biomimetic engineering
approaches for detecting and eliminating autoimmune T cell responses. Our goals here will be to develop
novel applications using our 1st generation 5MCAR technology and to iterate on the 5MCAR platform through the
engineering and testing of 2nd generation 5MCARs. Specifically, we will: 1) determine if using 5MCARs to redirect
central memory CD8+ T cells, stem cell memory CD8+ T cells, or Tregs are most effective at preventing T1D in
preclinical models; 2) use 5MCAR-CTLs as sentinels that can trafficking throughout the body and report on the
presence of pathogenic autoimmune CD4+ T cells prior to clinical symptoms; and, 3) engineer and test 2nd
generation 5MCARs that more closely mimic their native counterparts with the goal of improving 5MCAR
performance. When completed, the proposed work will provide valuable pre-clinical data for the therapeutic
potential of biomimetic 5MCAR-CTLs and 5MCAR-Tregs that are engineered based on evolution’s blueprint.

## Key facts

- **NIH application ID:** 10812390
- **Project number:** 5R01DK132537-03
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Michael S Kuhns
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $828,648
- **Award type:** 5
- **Project period:** 2022-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10812390

## Citation

> US National Institutes of Health, RePORTER application 10812390, Engineering 2nd generation 5MCARs to monitor and treat Type-I Diabetes (5R01DK132537-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10812390. Licensed CC0.

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