# Project 1: Priming and propagating immunity against head and neck cancer using targeted radionuclide therapy

> **NIH NIH P50** · UNIVERSITY OF WISCONSIN-MADISON · 2022 · $367,423

## Abstract

ABSTRACT – PROJECT 1
We propose to systematically evaluate mechanisms of cooperative interaction and to optimize the potency of a
treatment regimen that combines a targeted radionuclide therapy (TRT) with immune checkpoint inhibition
(ICI; e.g. anti-PD-1) to enhance the anti-tumor immune response against metastatic or recurrent head
and neck squamous cell carcinoma (HNSCC). Moderate dose (8-12 Gy) external beam radiation therapy
(EBRT) is capable of eliciting an in situ vaccine effect, converting the targeted tumor into a nidus for enhanced
tumor antigen recognition. In preclinical and clinical studies, this results in diversification of the T cell receptor
(TCR) repertoire. Consequently, in preclinical studies, EBRT improves the response to ICIs. However, clinical
studies in HNSCC patients have not demonstrated a benefit from combining EBRT with ICIs. More is needed if
we aim to develop an effective approach to achieving consistent durable tumor control in patients with metastatic
or recurrent HNSCC. In pursuit of this goal, we propose to evaluate a new strategy to leverage the capacity of
radiation to enhance response to ICIs by using TRTs to deliver radiation to all tumor sites in settings of metastatic
disease. Our team has developed and led preclinical and clinical testing of a novel class of TRT using
alkylphosphocholine (APCh) analogs that are IV injected and deliver radiation to cancers in vivo. These show
tumor-selective uptake in most mammalian tumor cells and tumor locations, including primary and metastatic
sites of HNSCC. In our current SPORE grant we have confirmed the selective uptake and safety of delivering a
first generation APCh analog that binds halogen radionuclides (131I-NM404) in patients with HNSCC. We have
now developed a next generation APCh analog (NM600) that, compared to NM404, has more favorable
dosimetry due to reduced albumin binding and has the ability to chelate diverse radionuclides. Here we propose
to use NM600 to compare the capacity of distinct radionuclides to immuno-modulate HNSCC tumors in a manner
that augments response to ICIs and increases the diversity or clonality of the TCR repertoire among tumor
infiltrating lymphocytes. We hypothesize that NM600 will enhance the rate and depth of response to ICIs and
that this will correlate with effects on the TCR repertoire that are dependent on the ability of NM600 to modulate
tumor cell immune susceptibility by activating a type I IFN response. We expect that NM600 will also elicit
immunogenic cell death, local inflammation, and temporary depletion of suppressive regulatory T cells (Tregs)
from the tumor microenvironment. By comparing the relative capacity of distinct radionuclides to elicit these, we
will develop a fundamental understanding of the interactions of TRTs and anti-tumor immunity. In a phase I
clinical study, we will then test whether NM600 can be delivered safely in combination with anti-PD-1 and
enhance response to this immunotherapy. The insight...

## Key facts

- **NIH application ID:** 10495293
- **Project number:** 2P50CA278595-06A1
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Zachary Scott Morris
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $367,423
- **Award type:** 2
- **Project period:** 2016-08-02 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10495293

## Citation

> US National Institutes of Health, RePORTER application 10495293, Project 1: Priming and propagating immunity against head and neck cancer using targeted radionuclide therapy (2P50CA278595-06A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10495293. Licensed CC0.

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