# Spatiotemporal molecular elucidation of radiation-induced tumor microenvironment remodeling to en-hance immunotherapy in head and neck cancer

> **NIH CA R01** · PROVIDENCE HEALTH & SERVICES - OREGON · 2026 · $715,710

## Abstract

Project Summary
Recently we showed in HNSCC models that effective checkpoint blockade is dependent upon intact lymphatic
drainage for dendritic cell trafficking and that elective nodal radiation abrogated the effectiveness of
immunotherapy, possibly explaining the lack of efficacy seen in prior studies. Neoadjuvant immunotherapy
preserves draining lymphatics, however, emerging trials testing PD-1i prior to surgery have documented major
pathological response rates of only 5%. To enhance the effectiveness of single agent PD-1i, improve clinical
outcomes and explore the immunomodulatory capacity of hypofractionated radiation, we recently completed
a first in human phase I trial testing neoadjvuant immunoradiotherapy (NIRT) in locally advanced HPV+ and
HPV- HNSCC patients. Patients received nivolumab x 3 doses in combination with stereotactic body radiation
therapy (SBRT) to gross tumor volume of 8Gy x5 or 8Gy x3, followed by definitive surgical resection.
Astonishingly, the pathologic complete response rate in HPV+ patients was 90% and no patient required
adjuvant radiation or chemoradiation. A cohort of 5 patients with stage III-IVA HPV-negative HNSCC treated
with 8GyX3 plus nivolumab demonstrated a 60% major pathologic (>25%) response and clinical to pathologic
downstaging of 100%. Transcriptional signatures from these surgical specimens compared to baseline are
characterized by increased phagocytic and macrophage activation pathways, Th1 and Th2 cell differentiation,
antigen presentation and peptide loading onto MHC class I, as well as a loss of cell proliferation pathways that
are distinctly different from those treated with radiation alone, strongly suggesting a synergistic effect. Given
our previous work showing that prognosis of patients with HPV- HNSCC is significantly affected by spatial
interactions between the immune effector and suppressor cells in the tumor microenvironment (TME), particularly
tumor-reactive, antigen-specific CD8 T-cells, we hypothesize th

## Key facts

- **NIH application ID:** 11298415
- **Project number:** 1R01CA301042-01A1
- **Recipient organization:** PROVIDENCE HEALTH & SERVICES - OREGON
- **Principal Investigator:** Richard Bryan Bell; Joseph A Califano; Thomas  Duhen; Brian Donald Piening
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** CA
- **Fiscal year:** 2026
- **Award amount:** $715,710
- **Award type:** 1
- **Project period:** 2026-05-01T00:00:00 → 2031-04-30T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11298415

## Citation

> US National Institutes of Health, RePORTER application 11298415, Spatiotemporal molecular elucidation of radiation-induced tumor microenvironment remodeling to en-hance immunotherapy in head and neck cancer (1R01CA301042-01A1). Retrieved via AI Analytics 2026-07-10 from https://api.ai-analytics.org/grant/nih/11298415. Licensed CC0.

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