# Targeting miRNA-loaded exosomes to HNSCC with Dsg2-directed scFv fusion proteins

> **NIH NIH R21** · THOMAS JEFFERSON UNIVERSITY · 2024 · $429,000

## Abstract

PROJECT SUMMARY/ABSTRACT
Advances in immunotherapy, especially PD1/PD-L1 immune-checkpoint inhibitors (ICI), are revolutionizing the
approach to personalized treatment for head and neck squamous cell carcinomas (HNSCC) with significant
positive clinical results. However, a large percentage of HNSCC patients still receive no benefit from this
treatment due to undefined mechanisms of resistance. Designing personalized targeted therapies with verified
biomarkers has been challenging due to the complex molecular etiology of the disease. Thus, there is an urgent
need to define resistance mechanisms operating within the tumor microenvironment (TME) to develop new
therapeutic paradigms that can effectively and safely treat HNSCC. Our long-term goal is to understand the roots
of pathogenic signaling during HNSCC progression. This proposal is based substantial published and preliminary
data showing that cadherin desmoglein 2 (Dsg2) modulates cell growth, survival, and metastasis and is
upregulated in many cancers including HNSCC where Dsg2 is often found overexpressed at the aggressive
leading edge of the tumors. Most importantly, mAb targeting Dsg2 inhibits tumor development in xenograft
model. Using these mAb we recently generated the anti-Dsg2 scFv CAR construct and the resultant Dsg2 CAR-
T cells not only recognized SCC cells but had robust in vitro and in vivo antitumor activity. Mounting evidence
suggests that exosomes or small extracellular vesicles (sEV) regulate local and systemic processes impacting
tumor progression and therapeutic outcomes. This proposal is based on solid preliminary data obtained from an
ICI clinical trial where sEV were purified from patients’ plasma and subjected to miRNAseq revealing an increase
in miR-155-5p (miR-155) in HPVneg patients that responded to treatment. miR-155 targets Dsg2 and PD-L1
mRNAs and their translation, suggesting that miR-155-loaded sEV could have antitumor activity. Our working
hypothesis is that engineered extracellular vesicles (eEV) carrying the Dsg2scFv-CD63 fusion proteins on the
surface and loaded with miR-155 can be harnessed for therapeutic treatment of Dsg2-overexpressing cancers.
The hypothesis and goal will be addressed in two Specific Aims designed to: 1) Engineer Dsg2scFv/miR-155
eEV and 2) Determine the antitumor activity of Dsg2scFv/miR-155 eEV. This proposal will deliver innovations in
defining blood-borne molecules that modulate ICI resistance in HNSCC patients, along with an opportunity to
rationally leverage this new knowledge through a unique proof-of-concept sEV therapy which represents a
cutting edge of the field.

## Key facts

- **NIH application ID:** 10811446
- **Project number:** 1R21DE033558-01A1
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** My Georgia Mahoney
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $429,000
- **Award type:** 1
- **Project period:** 2024-09-15 → 2026-09-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10811446

## Citation

> US National Institutes of Health, RePORTER application 10811446, Targeting miRNA-loaded exosomes to HNSCC with Dsg2-directed scFv fusion proteins (1R21DE033558-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10811446. Licensed CC0.

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