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

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $542,305

## 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 reduces and metabolically refines
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. In Aim 1, we will determine whether liver SBRT
combined with ipilimumab and nivolumab reverses hepatic and systemic immune dysfunction in patients
enrolled on our investigator initiated clinical trial by correlating tumoral and peripheral blood immune changes
with response. In Aim 2, we will determine how liver SBRT combined with ipilimumab and nivolumab reverses
hepatic and systemic immune dysfunction in preclinical models of liver metastases. In Aim 3, we will determine
whether liver SBRT modulates hepatic myeloid purine production and signaling to promote immune responses
in metastatic melanoma. The completion of these aims as well as the associated clinical trial will establish the
safety of liver SBRT with ipilimumab and nivolumab, provide preliminary efficacy measures of combination
therapy, allow the development of biomarkers of response in preclinical models of liver metastases, and
evaluate biomarkers of response in patients. The ultimate goal of this work is to test rationally-developed novel
combination of radiotherapy and ICI in hopes of improving the care of melanoma patients with liver metastases
who are resistant to immunotherapy.

## Key facts

- **NIH application ID:** 10837902
- **Project number:** 5R01CA276217-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** THEODORE S LAWRENCE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $542,305
- **Award type:** 5
- **Project period:** 2023-05-05 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10837902

## Citation

> US National Institutes of Health, RePORTER application 10837902, Ablating Liver Metastases with SBRT to Enhance Immune Checkpoint Blockade in Melanoma (5R01CA276217-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10837902. Licensed CC0.

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