# Focused Ultrasound Regimens that Synergize with Melanoma Immunotherapy

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2021 · $648,963

## Abstract

Immunotherapies (ITx) for melanoma have led to marked improvements in clinical outcomes. However,
objective response rates remain quite low (10-30%) because T-cells fail to infiltrate metastases in many patients.
Thus, the translation of adjunct approaches that enhance T-cell infiltration and/or lift the immunosuppressive
tumor microenvironment could vastly expand the population of melanoma patients exhibiting durable responses
to immunotherapy. Toward this goal, we hypothesize that perturbation of the melanoma microenvironment with
focused ultrasound (FUS), applied in energy regimens designed to elicit thermal ablation (T-FUS) and/or
microbubble cavitation (M-FUS), can stimulate immunologic responses that are both intrinsically therapeutic and
synergistic with translatable immunotherapies. Indeed, our pilot studies indicate that, even when applied to only
a small fraction of tumor volume, both T-FUS and M-FUS cooperate with the immune system to control
melanoma.
 This proposal is comprised of 3 specific aims that will serve to define differences in the innate and
adaptive immune responses that are elicited by applying different FUS energy regimes to tumors, identify barriers
to tumor immunity, and ascertain treatment protocols that more effectively combine FUS energy regimes with
adjunct immunotherapies for treating metastatic melanoma. Specific Aim 1 will first characterize thermal and
mechanical energy deposition generated during the application of T-FUS and M-FUS to B16F10 melanoma.
Then, using bilateral melanoma tumor models, we will identify T-FUS and M-FUS “ablation fractions” that, when
combined with first line αPD1 immunotherapy for melanoma, yield most efficacious immunological control of a
distant tumor. These ablation fractions will be carried forward through the rest of the proposal. Specific Aim 2
will entail determining the impact of the selected FUS energy regimes with αPD1 on discrete factors that influence
the sequential steps involved in the activation, expansion, and recruitment of T cells to the microenvironments
of FUS-treated and distant tumors. In turn, this will help us define optimized protocols for immune cell activation
and understand aspects of FUS modalities that are beneficial or detrimental to T cell-mediated tumor control.
Additional studies under Aim 2 will assess the mechanisms of adaptive resistance elicited by application of FUS
in these selected energy regimes. This will allow us to understand the diversity and intensity of compensatory
anti-inflammatory responses to FUS, which will be a critical aspect in optimizing the combination of FUS with
anti-tumor immunotherapy. Finally, Specific Aim 3 will both ascertain the ability of FUS to promote antibody
entrance to tumor and utilize information from previous aims to identify and test combinations of selected FUS
energy regimens and immunotherapeutic drugs in treatments that we hypothesize will yield most effective control
of disseminated tumors. We believe the ...

## Key facts

- **NIH application ID:** 10186745
- **Project number:** 5R01EB030007-02
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** TIMOTHY N BULLOCK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $648,963
- **Award type:** 5
- **Project period:** 2020-07-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10186745

## Citation

> US National Institutes of Health, RePORTER application 10186745, Focused Ultrasound Regimens that Synergize with Melanoma Immunotherapy (5R01EB030007-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10186745. Licensed CC0.

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