# Co-targeting the HER3 oncogenic signaling circuitry and PD-1 as a novel multimodal precision immunotherapy for HNSCC

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2022 · $489,974

## Abstract

Summary
Despite recent advances in treatment, the overall mortality for head and neck squamous cell carcinoma
(HNSCC) remains high and current treatment regimens incur significant long-term morbidity. Targeting the
immune checkpoint PD-1 with pembrolizumab and nivolumab has revolutionized HNSCC treatment. However,
the overall response rate of these immunotherapies remains low, around 15-20%. This highlights the urgent
need to identify novel therapeutic options for HNSCC to improve mortality, reduce morbidity, and enhance the
activity and response rate of immune oncology (IO) approaches for HNSCC. We hypothesize that targeting
HNSCC oncogenic signaling networks and disabling their immune evasive mechanisms may increase the
response to anti-PD-1 treatment as part of a novel rational therapeutic strategy. In this regard, our laboratory
contributed to the discovery that the persistent activation of the PI3K/mTOR signaling circuitry is the most
frequent dysregulated signaling mechanism in HNSCC, and that mTOR inhibition exerts potent antitumor activity
in multiple experimental HNSCC model systems and in a Phase 2 clinical trial (NCT01195922). Remarkably,
~20% of HNSCC lesions harbor driver PIK3CA mutations encoding active PI3Kα subunits, and yet ~90% of
HNSCC lesions exhibit aberrant PI3K/mTOR pathway signaling. In search for the underlying mechanisms, we
conducted a kinome wide RNAi screen, which revealed that persistent HER3 tyrosine phosphorylation and
association with PI3Kα sustain pathway activation in most of the HNSCC lesions. Indeed, HER3 is highly
expressed and persistently activated in most HNSCC lesions, correlating with poor prognosis. The best-in-class
anti-HER3 monoclonal antibody CDX-3379 inhibits the ligand-dependent and -independent activation of human
and murine HER3 by locking HER3 in its auto-inhibited configuration, and has demonstrated pharmacodynamic
and clinical activity in HNSCC patients. CDX-3379 exhibits potent antitumor activity in PIK3CA wild type HNSCC
tumor xenografts and patient derived xenografts (PDXs). Furthermore, we have obtained strong preliminary
results supporting that CDX-3379 administration 1) abolishes PI3K-mTOR signaling, 2) reverses the immune
evasive HNSCC microenvironment, and 3) can result in complete remission when combined with anti-PD-1
therapies in recently developed syngeneic mouse HNSCC models. Our premise is that co-targeting the HER3
signaling circuitry combined with anti-PD-1 blockade may represent a novel multimodal precision therapeutic
approach for HNSCC aimed at achieving durable responses and cancer remission. We will now aim 1) to
elucidate the contribution of genomic alterations in the PI3K-mTOR signaling network to anti-HER3 sensitivity
and resistance, and 2) to establish the impact of targeting and co-targeting the HER3-PI3K/mTOR signaling
network on the tumor immune microenvironment and response to PD-1 blockade, aiming at achieving a single
cell level understanding of the anti-cancer ...

## Key facts

- **NIH application ID:** 10304190
- **Project number:** 5R01CA247551-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Ezra Cohen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $489,974
- **Award type:** 5
- **Project period:** 2019-12-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10304190

## Citation

> US National Institutes of Health, RePORTER application 10304190, Co-targeting the HER3 oncogenic signaling circuitry and PD-1 as a novel multimodal precision immunotherapy for HNSCC (5R01CA247551-03). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10304190. Licensed CC0.

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