# Immunoengineering Next-Generation Cancer Therapies with Focused Ultrasound

> **NIH NIH DP5** · UNIVERSITY OF VIRGINIA · 2022 · $403,750

## Abstract

Project Abstract
Metastatic breast cancer (BrCa) is the 2nd most prevalent cause of cancer mortality in women in the United
States, with a 5-year overall survival of only 22%. Though cancer immunotherapies are capable of generating
durable responses across a variety of cancer types, immunologic rejection of BrCa is rare and spontaneous
regression unusual. Thus, there exists a strong precedent for allied combinatorial therapy paradigms that
potentiate immunotherapy (ITx) by boosting tumor immunogenicity and/or curbing immunosuppressive
mechanisms. In this proposal, we will systematically assess the capacity of focused ultrasound (FUS) - a
technique for non-invasive, non-ionizing acoustic energy deposition into tumors – to potentiate adaptive immunity
against BrCa metastases and synergize with selected immunotherapies. UVA is a world leader in FUS ITx
research, with two “first-in-human” clinical trials underway to evaluate combinations of FUS with PD1 blockade
in solid tumors (including metastatic BrCa) and a third trial pending approval to evaluate FUS and gemcitabine
for immune-mediated control of BrCa tumors. These trials are accompanied by a companion imaging trial
designed to evaluate CD8+ T cell infiltration in patients’ tumor deposits via PET/CT, an approach that will also
be integrated into our pre-clinical studies. To this end, this proposal leverages these clinical trials as well as a
robust pre-clinical program to fortify a highly translational research pipeline rooted in the domains of immunology,
molecular imaging, liquid biopsy and radiogenomics. With this toolkit, we intend to design and implement
FUS+ITx combinations that offer the potential for quantum improvements in metastatic BrCa therapy. This is
achieved in three Specific Aims. In Specific Aim 1, we will expand on intriguing early clinical and pre-clinical
findings to identify FUS regimens that, when combined with myeloid-targeted therapies, augment the efficacy of
chimeric antigen receptor (CAR) T cell therapy against primary and disseminated BrCa tumors (e.g. brain
metastases). In Specific Aim 2, we will engineer FUS-based theranostic technologies for liquid biopsy in BrCa in
order to (i) discover novel biomarkers of response to FUS and ITx (ii) enable liquid biopsy in settings with low
basal levels of circulating tumor biomarkers. Finally, in Specific Aim 3, we will construct machine learning
frameworks that integrate radiological data with genomic data from liquid biopsy specimens (e.g. radiogenomics)
to advance BrCa precision care with FUS and ITx. The highly innovate aims of this proposal lend to a systematic
approach for advancing the role of FUS in CAR T cell therapy, cancer biomarker discovery and personalized
ITx, thereby promising to improve the lives of metastatic breast cancer patients.

## Key facts

- **NIH application ID:** 10488685
- **Project number:** 5DP5OD031846-02
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Natasha Diba Sheybani
- **Activity code:** DP5 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $403,750
- **Award type:** 5
- **Project period:** 2021-09-14 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10488685

## Citation

> US National Institutes of Health, RePORTER application 10488685, Immunoengineering Next-Generation Cancer Therapies with Focused Ultrasound (5DP5OD031846-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10488685. Licensed CC0.

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