# Targeting STAT3 to enhance anti-tumor immunity

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $636,402

## Abstract

ABSTRACT
Head and neck squamous cell carcinoma (HNSCC) is a common and lethal cancer, where 5-year survival
rates have lingered at roughly 40-60% for several decades. Our long-term objective is to develop effective,
well-tolerated agents and strategies to improve the outcomes of patients with HNSCC. The recent approval of
the PD-1 checkpoint inhibitors nivolumab and pembrolizumab for HNSCC suggests that targeting central
mediators of immunosuppression in the tumor microenvironment will lead to significant improvements in
treatment. Inhibition of the oncogenic transcription factor STAT3 represents a promising new strategy for
relieving immunosuppression. STAT3 is hyperactivated in HNSCC, where it contributes to tumor growth,
production of immunosuppressive cytokines, and poor prognosis. STAT3 is also hyperactivated in tumor
infiltrating immune cells. Conditional deletion of stat3 in murine hematopoietic cells has revealed potent
immunosuppressive roles for STAT3 in multiple immune cell populations. Thus, selective targeting of STAT3
may yield a three-fold anti-tumor benefit: a) direct inhibition of tumor cell growth, b) inhibition of cell-
autonomous immunosuppression in immune cells, and c) relief of immunosuppressive cross-talk between
tumor and immune cells. However, currently available STAT3 inhibitors either lack potency and specificity, or
cannot be delivered systemically. To overcome this obstacle we designed a 15-bp duplex oligonucleotide, the
STAT3 decoy, which resembles a STAT3 response element, binds selectively to activated STAT3, induces
HNSCC apoptosis, and suppresses the growth of xenograft tumors. A Phase 0 trial involving intratumoral
injection of this STAT3 decoy demonstrated downmodulation of STAT3 target genes in HNSCC tumors. A
cyclic version of STAT3 decoy exhibits improved stability and nuclease resistance, and inhibits the growth of
xenograft tumors following systemic delivery to immunodeficient mice. The impact of the cyclic STAT3 decoy
on the immune system has never been studied, limiting the design of further clinical trials with this promising
anti-cancer agent. We will utilize immunocompetent murine models of HNSCC to rigorously evaluate the
effects on the immune system of cyclic STAT3 decoy, alone and in combination with PD-1 inhibition. In
addition, we will evaluate safety, immune effects and potential efficacy, of the cyclic STAT3 decoy in a unique
and valuable animal model of naturally occurring HNSCC in pet cats. Our studies will test the hypothesis that
targeted inhibition of STAT3 via systemic administration of cyclic STAT3 decoy will enhance anti-tumor
immunity in immunocompetent mouse models of HNSCC and augment the effects of PD-1 checkpoint
inhibition, while exhibiting minimal toxicity in pet cats with naturally occurring HNSCC. Results from our
studies will determine the potential for relieving immunosuppression in HNSCC using cyclic STAT3 decoy,
while laying the foundation for clinical advancement of this ...

## Key facts

- **NIH application ID:** 9994278
- **Project number:** 5R01DE028289-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Jennifer Rubin Grandis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $636,402
- **Award type:** 5
- **Project period:** 2019-08-13 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9994278

## Citation

> US National Institutes of Health, RePORTER application 9994278, Targeting STAT3 to enhance anti-tumor immunity (5R01DE028289-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/9994278. Licensed CC0.

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