# Leveraging Focused Ultrasound to Sensitize Refractory Melanoma to Immunotherapy

> **NIH NIH F30** · UNIVERSITY OF VIRGINIA · 2020 · $36,127

## Abstract

Abstract: The incidence and mortality rates for melanoma have been increasing for the last 30 years, with
metastatic melanoma harboring a 5-year survival rate between 5 and 10%. These tumors develop mechanisms
to avoid immune surveillance, including upregulation of inhibitory checkpoint ligands, increased production of
immune-modulating cytokines, and decreased antigen expression. The advent of immunotherapies, drugs that
overcome these immunosuppressive mechanisms such as anti-PD1, has offered substantial promise to
improve patient outcomes. Unfortunately, variable response rates and the possibility for severe autoimmune
reactions have hindered the efficacy of immunotherapies, necessitating identification of adjuvant therapeutic
modalities. Focused Ultrasound (FUS), a non-invasive tissue ablation technology, has substantial potential to
meet this need. Recent studies showing FUS enhances the immunogenicity of the tumor microenvironment
(TME) have led to hypotheses that FUS could convert tumors from immunologically “cold” to “hot”, rendering
them responsive to immunotherapy. Currently the therapeutic potential for FUS-immunotherapy combination
remains unrealized due to incomplete i) mechanistic knowledge of FUS immunogenicity, ii) appreciation of
compensatory resistance to FUS, and iii) optimization of the immunostimulatory profile induced in the TME. To
overcome these barriers, high throughput transcriptomic and single cell methods will be performed in murine
melanoma at multiple times post-FUS. These studies will be performed in the context of single or multiple FUS
application to test whether repeated treatment, an understudied strength of FUS over radiation, can be
leveraged to optimize immunogenicity. Insight gained from these studies will permit both selection of a FUS
regimen that is maximally immunogenic and an immunotherapeutic with which to combine it, based explicitly
on identified mechanisms of immunomodulation. The ability of selected FUS-immunotherapy combination
strategies to provide primary and systemic tumor growth control will be systematically evaluated in two
transplantable murine melanoma models, both of which are insensitive to checkpoint blockade alone. This
represents an important step in leveraging FUS to sensitize refractory melanoma to immunotherapy.
 This proposal involves scientific, professional, and clinical training. The PI will complete formal
coursework in cancer immunotherapy and receive direct guidance from immunologist collaborators at weekly
meetings. The PI plans to communicate important findings at national and international conferences and in
journal manuscripts. Finally, the PI will frequently shadow a clinical oncologist and maintain clinical skills.
 Research will be carried out under the guidance of therapeutic ultrasound expert, Dr. Richard Price at
the University of Virginia, a highly cooperative environment that inspires patient-centric research. Indeed, the
proposed work will be done in collaborati...

## Key facts

- **NIH application ID:** 9911274
- **Project number:** 1F30CA247254-01
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Alexander Sean Mathew
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $36,127
- **Award type:** 1
- **Project period:** 2020-06-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9911274

## Citation

> US National Institutes of Health, RePORTER application 9911274, Leveraging Focused Ultrasound to Sensitize Refractory Melanoma to Immunotherapy (1F30CA247254-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9911274. Licensed CC0.

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