# MyD88 fusion protein with antigen specific T Cell therapy for enhanced response in solid tumors

> **NIH NIH R43** · LUMINARY THERAPEUTICS, INC. · 2020 · $397,422

## Abstract

Abstract
Despite recent advances in cancer treatment, patients with pancreatic cancer still do not have effective options
for treatment and fewer than 10% survive more than five years. T cell receptor (TCR) based therapies have
achieved positive responses in a subset of patients with advanced solid tumors, representing a promising
approach for pancreatic cancer. However, low level antigen expression and the immunosuppressive tumor
microenvironment impair antigen recognition and limit T cell persistence and function, impeding consistent
success against solid tumors. To surmount these challenges, we have devised a strategy to improve anti-tumoral
responses in a T cel- based platform. Mesothelin (MSLN) is expressed by 80-85% of pancreatic tumors, making
it an attractive TCR target for the treatment of pancreatic cancer. We have validated the cytolytic activity of T
cells engineered with human HLA-A2 restricted MSLN specific TCRs against MSLN expressing pancreatic tumor
cells in vitro. Previous work from our group with murine Msln specific TCRs in a mouse model of pancreatic
cancer further demonstrated engineered T cells reduced tumor burden in vivo but lacked persistence. We thus
seek to develop a novel immunotherapy that combines our MSLN specific TCRs with the uniquely potent co-
stimulatory properties of a synthetic CD8α:MyD88 fusion protein. In transgenic mice, tumor reactive T cells
expressing the CD8α:MyD88 fusion protein demonstrate antigen specific increases in cytokine production,
proliferation, and cytotoxicity, eliciting durable tumor regression compared to controls. To evaluate this approach
as a clinically relevant immunotherapy platform for pancreatic cancer we will utilize a novel non-viral genetic
engineering approach to co-express MSLN specific TCRs with the CD8α:MyD88 fusion protein in primary human
T cells. Vector configuration will be optimized by evaluating stable TCR and CD8α:MyD88 fusion surface
expression, as well as T cell phenotype, function, and cytotoxicity against pancreatic cancer cells in vitro.
Optimized vector configurations will be carried forward and tested in preclinical animal models to evaluate safety
and efficacy in support of follow-on IND enabling studies. If successful, our efforts will lead to an innovative new
immunotherapeutic strategy to overcome challenges that have prevented meaningful improvement in pancreatic
cancer patient outcomes.

## Key facts

- **NIH application ID:** 10080228
- **Project number:** 1R43CA254794-01
- **Recipient organization:** LUMINARY THERAPEUTICS, INC.
- **Principal Investigator:** Samantha Dunmire
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $397,422
- **Award type:** 1
- **Project period:** 2020-09-08 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10080228

## Citation

> US National Institutes of Health, RePORTER application 10080228, MyD88 fusion protein with antigen specific T Cell therapy for enhanced response in solid tumors (1R43CA254794-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10080228. Licensed CC0.

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