# Ablating Liver Metastases with SBRT to Enhance Immune Checkpoint Blockade in Melanoma

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $82,478

## Abstract

Abstract
Immune checkpoint inhibitors (ICI) have revolutionized the care of patients with metastatic
melanoma. Unfortunately, not all patients benefit from this therapy, and rational combinatorial
strategies to enhance ICI efficacy in therapy non-responders are needed. We and others have shown
that patients with liver metastases derive limited clinical benefit from ICI across a wide variety of
disease types. In preclinical colorectal and melanoma models, we discovered that liver metastases
cause immunotherapy resistance by siphoning tumor-specific T cells from systemic circulation.
Within the liver, activated antigen-specific CD8+ T cells undergo apoptosis. Consequently, liver
metastases create a systemic immune desert in preclinical models. Similarly, patients with liver
metastases have reduced peripheral T cell numbers and diminished tumoral T cell diversity and
function. In preclinical models, liver-directed radiotherapy eliminates immunosuppressive hepatic
macrophages, increases hepatic T cell survival, and reduces hepatic siphoning of T cells. The central
hypothesis of this proposal is that liver SBRT address ICI resistance in melanoma patients with liver
metastases. We are now prospectively testing this strategy of combining liver SBRT with ipilimumab
and nivolumab in melanoma patients with liver metastases. We have recently determined that liver
metastasis is associated with a significant accumulation of neutrophils in the liver, and that this is
mirrored by significantly higher circulating neutrophils in metastatic melanoma patients with liver
metastases. We anticipate that maximal sensitivity to immune checkpoint inhibitors (ICI) can only be
achieved by addressing both myeloid resistance mechanisms. In Aim 1, we will determine whether
liver SBRT combined with ipilimumab and nivolumab reverses hepatic and systemic neutrophil
dysfunction in our preclinical murine model by measuring number and function of circulating and
hepatic neutrophils, as well as assessing programs of myeloid signaling. In Aim 2, we will determine
whether liver SBRT modulates hepatic neutrophil purine metabolism and signaling to promote
immune responses in metastatic melanoma, and whether existing hepatic myeloid purine production
affects liver neutrophil accumulation. The completion of these aims will provide preliminary efficacy
measures of combination therapy and allow the development of biomarkers of response in preclinical
models of liver metastases. The ultimate goal of this work is to test rationally-developed novel
combination of radiotherapy and IC in hopes of improving the care of melanoma patients with liver
metastases who are resistant to immunotherapy.

## Key facts

- **NIH application ID:** 10943987
- **Project number:** 3R01CA276217-02S1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Michael Daniel Green
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $82,478
- **Award type:** 3
- **Project period:** 2023-05-05 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10943987

## Citation

> US National Institutes of Health, RePORTER application 10943987, Ablating Liver Metastases with SBRT to Enhance Immune Checkpoint Blockade in Melanoma (3R01CA276217-02S1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10943987. Licensed CC0.

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