# Therapeutic Targeting of Macrophage PI3Kgamma in HNSCC

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2024 · $522,215

## Abstract

Head and neck squamous cell carcinoma (HNSCC) is a deadly and disfiguring disease that will accounted for
more than 800000 cases worldwide in 2023. The sixth most common cancer worldwide, HNSCC continues to
increase, in part due to human papillomavirus (HPV) associated oropharynx cancers. The current standard
therapeutic regimens of surgery, chemotherapy, therapy and anti-PD-1 therapy are associated with significant
morbidity and loss of quality of life, with only modest 5-year survival rates. Immune therapy has offered new
options for HNSCC patients; treatment with T cell checkpoint inhibitors or therapeutic vaccines has led to gains
in survival for a portion of treated patients. However, the majority of HNSCC patients are resistant to these
therapies. Improved therapeutic approaches that target mechanisms of treatment escape hold promise for this
disease. We have found that HNSCC tumors are abundantly infiltrated by immune suppressive myeloid cells,
including monocytes, macrophages, and granulocytes, which inhibit T cell recruitment and activation, leading to
immune suppression and resistance to checkpoint inhibitors in HNSCC. Inhibitory targeting of
phosphatidylinositol-4,5-bisphosphate 3-kinase, PI3Kgamma (PI3Kg), a myeloid cell specific PI3K isoform,
reduces myeloid cell accumulation and converts remaining myeloid cells into pro-inflammatory cells, leading to
T cell activation and tumor inhibition in mouse models of HPV+ and HPV- HNSCC tumors. PI3Kg inhibition
synergizes with checkpoint inhibitors, stimulating T cell recruitment, activation, and memory formation. Based on
these findings, the PI3Kg inhibitor, IPI-549 (eganelisib), was developed as an immune oncology therapeutic and
has exhibited anti-tumor responses in Phase 1 and 2 clinical trials for the treatment of newly diagnosed cancer.
Spatial transcriptomics of HNSCC patient tissues from clinical trials showed us that PI3Kg antagonism enhances
biomarkers of myeloid cell and T cell activation in HNSCC patients. These bench to bedside to bench studies
identified novel myeloid cell, T cell and B cell biomarkers of response to PI3Kg inhibitors, as well as biomarkers
of treatment resistance. However, they also revealed potential mechanisms of therapeutic resistance. To
advance our understanding of PI3Kg inhibition in HNSCC, we propose to test the hypothesis that inhibitory
targeting of PI3Kg in tumor associated macrophages promotes both humoral and cellular immune responses that
suppress HNSCC tumor cell survival but also activates novel mechanisms of therapeutic resistance. The specific
aims of this proposal are: 1) To determine critical molecular and cellular regulators of PI3Kg mediated tumor
immune suppression in mouse models of HPV+ and HPV- HNSCC 2) To discover and target mechanisms of
resistance to PI3Kg inhibition in models of head and neck cancer.3) To identify circulating biomarkers of response
and resistance to PI3Kg inhibition that reflect intratumoral tumor biology in HNSCC pa...

## Key facts

- **NIH application ID:** 10811486
- **Project number:** 2R01CA226909-06A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Kathryn Ann Gold
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $522,215
- **Award type:** 2
- **Project period:** 2018-04-17 → 2028-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10811486

## Citation

> US National Institutes of Health, RePORTER application 10811486, Therapeutic Targeting of Macrophage PI3Kgamma in HNSCC (2R01CA226909-06A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10811486. Licensed CC0.

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