# Molecularly targeted photothermal ablation to enhance the therapeutic efficacy of immunomodulatory therapies in hepatocellular carcinoma

> **NIH NIH R21** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2020 · $200,000

## Abstract

ABSTRACT
 Hepatocellular carcinoma (HCC) is the fastest growing cause of cancer-related deaths in
the US. Due to intrinsic tumor resistance and underlying liver dysfunction, the availability of
effective systemic chemotherapies for HCC remains very limited. Immunotherapy is a promising
new treatment approach for HCC, but there are numerous barriers to immunotherapy in HCC,
including an immunosuppressive microenvironment and the “immunotolerance” of the liver.
Thermal ablation can overcome these barriers by inducing hyperthermic cell stress, resulting in
immunogenic tumoral cell death. However, conventional ablation modalities are limited by their
lack of tumoral specificity, resulting in unavoidable thermal injury to adjacent normal tissues. This
thermal injury can stimulate systemic tumor growth through the release of oncogenic
inflammatory cytokines. Consequently, there is an unmet need for a tumor-specific ablation
modality ideally suited to “priming” the adaptive immune system against HCC. An ideal modality
would maximize tumor hyperthermia, thus augmenting tumor-specific immune stimulation, and
minimize thermal injury to adjacent tissue, thus preventing systemic tumor stimulation.
 By capitalizing on the exceptional localization of the clinically approved fluorescent drug
indocyanine green (ICG) to HCC, we propose an ICG-based molecularly targeted photothermal
ablation (MTPA) modality that will maximize tumor hyperthermic stress but minimize thermal
injury to adjacent liver tissue. We hypothesize that MTPA will synergize with immune checkpoint
inhibitor therapy and result in systemic tumoricidal immune activation with immunologic “memory”
but not the off-target oncogenic effects seen in conventional ablation. We will explore the
adaptive immune response following MTPA in an orthotopic murine model of HCC in a
background of liver cirrhosis. We will also test for hepatocyte injury and off-target oncogenic
effects following MTPA compared to conventional ablation.
 This proposal builds upon the Principal Investigator's expertise in thermal ablation as well
as optical molecular imaging. If successful, the proposed studies will establish a new clinically
translatable, tumor-specific ablation modality for HCC. They will also greatly expand our
knowledge of the immune/inflammatory ramifications of hyperthermia, knowledge that can be
leveraged into tailoring locoregional therapies that result in maximal anti-tumor immune response.
These advances can be combined synergistically with immune therapies to provide a potent
systemic treatment for patients with advanced HCC.

## Key facts

- **NIH application ID:** 9852331
- **Project number:** 5R21EB026089-02
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Rahul Anil Sheth
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $200,000
- **Award type:** 5
- **Project period:** 2019-01-19 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9852331

## Citation

> US National Institutes of Health, RePORTER application 9852331, Molecularly targeted photothermal ablation to enhance the therapeutic efficacy of immunomodulatory therapies in hepatocellular carcinoma (5R21EB026089-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9852331. Licensed CC0.

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