# Engineered TCR-Treg Cell Therapies Targeting Type 1 Diabetes Autoantigens

> **NIH NIH R43** · GIGAMUNE, INC. · 2022 · $300,000

## Abstract

PROJECT SUMMARY
Project Title: Engineered TCR-Treg Cell Therapies Targeting Type 1 Diabetes Autoantigens
Organization: GigaMune Inc.
PI: Matthew J Spindler, Ph.D.
Engineered adoptive cell therapies including CAR-T and TCR-T cell therapies have shown strong clinical
responses in cancer patients with five FDA approved CAR-T cell therapies for hematological cancers and
numerous TCR-T cell clinical trials ongoing for the treatment of solid tumors. These new drugs have all leveraged
engineered cytotoxic T cells and are designed to directly kill cancer cells. In contrast to cytotoxic T cells, Tregs
function to locally suppress immune responses through antigen-specific activity. TCR engineered regulatory T
cells (TCR-Tregs) could be used for the treatment of patients with autoimmune disorders, not for killing target
cells but rather for preventing cells from being killed. However, in order to develop engineered TCR-Treg cell
therapies, there is a critical need in identifying autoantigen reactive TCRs to specifically direct Treg activity into
pancreatic islets where they can locally suppress the autoreactive cytotoxic T cells causing disease pathology.
Type 1 diabetes (T1D) autoantigens, including preproinsulin, IA-2, and GAD65, are ideal TCR-Treg cell targets
as they are specifically expressed in pancreatic islets and beta (b)-cells. These autoantigens are commonly
targeted by CD4 and CD8 T cells in T1D patients with peptide epitopes presented across many HLA alleles.
Importantly, recent studies have demonstrated that TCR clonotypes isolated from CD8+ T cells can redirect Treg
suppressive activity to class I HLA presented peptides. This suggests that engineered TCR-Tregs targeting T1D
autoantigens could suppress autoreactive cytotoxic T cells within the pancreatic islets. Therefore, a catalog of
TCR-Treg cell therapies targeting T1D autoantigens across different HLA alleles would provide a broadly
effective treatment for T1D patients.
The Specific Aim of this Phase I SBIR project is to develop a catalog of natural human TCRs that target T1D
autoantigens for use in TCR-engineered Treg cell therapies. GigaMune's unique technology uses microfluidics,
genomics, and mammalian display to generate millions-diverse, natively paired TCRab repertoire libraries. The
TCRab libraries are immortal, enabling repeated experimentation with a panel of antigens. This will expedite
discovery of rare anti-T1D TCRs.
The project is led by Dr. Matthew J. Spindler, an expert in immunogenomics and inventor of the GigaMune
technology and supported by serial entrepreneur and co-founder David Johnson (GigaGen). After completing
this Phase I SBIR project, GigaMune will further develop promising TCRs as TCR-Treg cell therapies, through
in vivo efficacy studies, in vitro safety studies, and manufacturing development.

## Key facts

- **NIH application ID:** 10545634
- **Project number:** 1R43AI170407-01A1
- **Recipient organization:** GIGAMUNE, INC.
- **Principal Investigator:** Matthew James Spindler
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $300,000
- **Award type:** 1
- **Project period:** 2022-08-11 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10545634

## Citation

> US National Institutes of Health, RePORTER application 10545634, Engineered TCR-Treg Cell Therapies Targeting Type 1 Diabetes Autoantigens (1R43AI170407-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10545634. Licensed CC0.

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