# Project 1: Hypoxia and metabolic dysregulation as a targetable barrier to immunotherapy in head and neck squamous cell carcinoma (HNSCC)

> **NIH NIH P50** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $305,980

## Abstract

PROJECT SUMMARY − PROJECT 1
 In recurrent and metastatic head and neck squamous cell carcinoma (R/M HNSCC), immune checkpoint
blockade has changed the standard of care, with trials from HN SPORE PI Dr. Robert Ferris and co-I (Project
2) Dr. Barbara Burtness pioneering the use of anti-PD-1 in this setting. Unfortunately, only a minority of
patients benefit, due to resistance to anti-PD-1 therapy, pointing to an urgent need to better understand the
tumor microenvironment. With HN SPORE support, first through a Developmental Research Program award
and later following elevation to Continuing Project 1, we have identified a connection between tumor
metabolism, hypoxia and T cell dysfunction that may be partially driving resistance to anti-PD-1 (Zandberg, et
al, ASCO 2020). To further investigate this question, we are proposing to conduct two newly designed, novel
therapeutic clinical trials within Project 1, in R/M HNSCC naïve to anti-PD-1 (HCC 18-190/NCT04114136) or
progressed on anti-PD-1 (HCC 18-156/NCT04326257). The former is a trial of metabolic modulators and anti-
PD1, the latter a trial of anti-PD-1 combined with either anti-CTLA4 or anti-LAG3. Utilizing these trials and pre-
clinical models of HNSCC, we will examine the following questions. First, what is the relationship between
anti-PD-1 resistance, tumor metabolism and hypoxia in HNSCC? With the assistance of Core B, we will
address this question via multiplexed tissue analysis in R/M HNSCC samples from our clinical trials as well as
radiomics-based approaches of determining tumor hypoxia. Second, does hypoxia promote resistance to
combinatorial immunotherapy in HNSCC? We will test how hypoxia may impede immunotherapy with
nivolumab plus relatlimab (anti-LAG3), or ipilimumab (anti-CTLA4) in R/M HNSCC patients who have
progressed on anti-PD-1, evaluating tissue before and after therapy. Third, can metabolically targeted therapy
be combined with anti-PD-1 to overcome anti-PD1 resistance in HNSCC? We will evaluate tumor samples
obtained before and after treatment with anti-PD-1 plus either metformin or rosiglitazone and determine
changes in tumor metabolism and hypoxia. We will also test combinatorial immunotherapy (as in Aim 2) with
metabolic modulation in pre-clinical HNSCC models rendered anti-PD1 resistant. Our trial of metabolic
inhibitors combined with anti-PD1 therapy, if positive, will directly lead to larger scale clinical studies, opening
up an entirely novel avenue of combinatorial immunotherapy; while the project as a whole will also provide a
platform for developing future personalized immunotherapy trials by adding metabolic analysis and/or
modulation as a component.

## Key facts

- **NIH application ID:** 10923899
- **Project number:** 5P50CA097190-18
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Greg M. Delgoffe
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $305,980
- **Award type:** 5
- **Project period:** 2004-07-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10923899

## Citation

> US National Institutes of Health, RePORTER application 10923899, Project 1: Hypoxia and metabolic dysregulation as a targetable barrier to immunotherapy in head and neck squamous cell carcinoma (HNSCC) (5P50CA097190-18). Retrieved via AI Analytics 2026-05-30 from https://api.ai-analytics.org/grant/nih/10923899. Licensed CC0.

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