# Molecular Targeted Radionuclide Therapy to Enhance Tumor Cell Susceptibility and Response to Immune Checkpoint Inhibition

> **NIH NIH P01** · UNIVERSITY OF WISCONSIN-MADISON · 2021 · $392,015

## Abstract

PROJECT SUMMARY – PROJECT 2
In a project that builds upon the ongoing collaborative progress of our multidisciplinary team, we will
systematically evaluate mechanisms of cooperative interaction and optimize the potency of treatment regimens
that combine targeted radionuclide therapies (TRT) with immune checkpoint inhibition (ICI; e.g. anti-PD-
1, anti-CTLA-4) to enhance the anti-tumor immune response against metastatic cancers. 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. This is at least in part dependent upon the capacity of EBRT to activate a type I interferon (IFN)
response in radiated tumor cells. However, clinical studies have not yet conclusively demonstrated a benefit from
combining EBRT with ICIs, and even in studies that suggest a benefit it is clear that more is needed if we aim to
develop an effective approach to eradicating metastatic disease for all cancer patients. In pursuit of such a goal,
we now propose to evaluate a next generation strategy to leveraging the capacity of radiation to enhance
response to ICIs by using TRTs to deliver radiation to all tumor sites in settings of metastatic disease. To begin
testing this approach, we will compare the relative capacities of different TRT agents to 1) activate a type I IFN
response in tumor cells, 2) augment response to ICIs, and 3) increase the diversity and clonality of the TCR
repertoire among tumor infiltrating lymphocytes. We hypothesize that TRT will enhance the rate and depth of
response to ICIs and that this will correlated with effects on the TCR repertoire that are dependent on the ability
of TRT to modulate tumor cell immune susceptibility by activating a type I IFN response. We expect that TRTs
will also elicit immunogenic cell death, local inflammation, and temporary depletion of suppressive regulatory T
cells (Tregs) from the tumor microenvironment (TME), and other Projects in this P01 will investigate those
mechanisms further. Here, we will compare the relative effects of TRT radionuclides and vectors in order to
develop a fundamental understanding of the interactions between these agents and anti-tumor immunity. In
particular, we will evaluate the potential impacts of tumor size, type, and number as well as the type of radioactive
decay products (e.g. α particle vs β particle vs γ-ray vs Auger electron), linear energy transfer (LET), dose, dose-
rate and half-life, and dose range. We will also examine the potential impact of the TRT vector, specifically testing
how changes in TRT distribution at the organism, tumor, and subcellular level affect anti-tumor immunity. The
insights and treatment regimens developed in these studies should enabl...

## Key facts

- **NIH application ID:** 10263247
- **Project number:** 5P01CA250972-02
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Zachary Scott Morris
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $392,015
- **Award type:** 5
- **Project period:** 2020-09-14 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10263247

## Citation

> US National Institutes of Health, RePORTER application 10263247, Molecular Targeted Radionuclide Therapy to Enhance Tumor Cell Susceptibility and Response to Immune Checkpoint Inhibition (5P01CA250972-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10263247. Licensed CC0.

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