# Ultrasound-Controlled Immunotherapy for Targeted Treatment of Solid Tumors

> **NIH NIH F30** · CALIFORNIA INSTITUTE OF TECHNOLOGY · 2021 · $51,036

## Abstract

Project Summary
Advances in synthetic biology have enabled the development of increasing numbers of cell-based diagnostic
and therapeutic tools. However, controlling these cells in vivo is difficult and current methods to communicate
with engineered cells either suffer from poor spatiotemporal resolution or require invasive operations. In order to
improve safety and efficacy of cell-based therapies, robust methods to control gene expression in vivo are
required. Temperature is a unique communication signal as it can be modulated with millimeter precision deep
within tissues non-invasively using focused ultrasound (FUS). In addition, cells have already evolved the ability
to sense changes in temperature through heat shock promoters (HSPs). These genetic elements are ubiquitous
across organisms, providing a platform to develop genetic circuits that will activate upon FUS heating. Combining
the spatial control offered by FUS with cellular engineering to confer thermal sensitivity will allow us to create
thermally responsive cells that will activate in specific locations following FUS treatment.
 One rapidly growing field that could benefit from spatially controlled gene expression is cell-based cancer
immunotherapy. Immunotherapy has recently emerged as a promising new class of cancer therapies with
transformative results in hematological malignancies. However, engineered cell-based immunotherapies such
as CAR T-cells and immunomodulatory agents such as cytokines must overcome significant challenges before
becoming more widely applicable for solid tumors. In recent clinical trials, CAR T-cells have attacked healthy
tissues if their targeted antigen is not tumor limited, resulting in massive peripheral toxicity and death. Systemic
cytokine therapy can also cause life-threatening adverse effects such as vascular leak syndrome. Both types of
immunotherapy could benefit from spatially controlled therapeutic expression.
 This project’s overall goal is to develop HSP-driven circuits in primary T-cells that will allow thermal stimuli
delivered by FUS to active therapeutic genes expression. Initial experiments will focus on developing T-cells in
vitro that will respond to bulk heating by transiently releasing cytokine to boost CAR performance in an autocrine
fashion or activating permanent CAR expression specifically in the tumor. We will accomplish this by developing
HSP driven circuits that feature drug induced transactivators or Cre Recombinase. After validating these circuits
in vitro, we will test their performance upon FUS treatment in vivo using a murine SKBR3 tumor model and an
anti-HER2 CAR. This model will allow us to develop and demonstrate the performance of robust, FUS-activated
primary T-cells with two distinct payload outputs. This proposed approach represents a novel combination of
cellular engineering and therapeutic ultrasound to spatiotemporally control cell-based immunotherapies with
direct application to solid tumor treatment. This tech...

## Key facts

- **NIH application ID:** 10142820
- **Project number:** 1F30CA250483-01A1
- **Recipient organization:** CALIFORNIA INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Justin Lee
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $51,036
- **Award type:** 1
- **Project period:** 2021-06-15 → 2023-06-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10142820

## Citation

> US National Institutes of Health, RePORTER application 10142820, Ultrasound-Controlled Immunotherapy for Targeted Treatment of Solid Tumors (1F30CA250483-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10142820. Licensed CC0.

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