# Building a New Therapeutic Paradigm for Hepatocellular Cancer by Dissecting the Interaction between Radiofrequency Ablation, Chemotherapy, and Immunotherapy

> **NIH VA I01** · HARRY S. TRUMAN MEMORIAL VA HOSPITAL · 2020 · —

## Abstract

Hepatocellular cancer (HCC) remains one of the deadliest cancers with limited clinical options. Due of
life style choices, living conditions, and/or environmental elements, risk factors for the development of HCC
cause the increased incidence in military service members, veterans, and their families with 10-fold higher than
the general population. Radiofrequency ablation (RFA) has emerged as a first line treatment option for patients
with HCC. When combined with modern imaging, RFA can be performed percutaneously or laparoscopically.
Image-guided RFA has the following significant advantages: lower morbidity, minimized physiologic insult of
surrounding tissues, reduced cost, short hospitalization time, and intra-procedural visualization for precise
targeting. However, incomplete ablation, tumor recurrence, and inferior outcomes persist, revealing that rational
combination with other therapeutic strategies is needed to more effectively treat HCC.
 Breakthroughs in cancer immunotherapy offer potential promise for HCC treatment, but no approaches
have been translated into clinical application. In situ RFA capably destroys tumor cells to release substantial
antigens that might modulate antitumor immunity. However, the resultant therapeutic immune response by RFA
alone is too modest to destroy established tumors. This is because tumors develop different mechanisms to
induce profound immunotolerance in the tumor microenvironment. Therefore, overcoming tumor-induced
immunotolerance is critically important for RFA-liberated antigens to prime powerful antitumor immune response.
 Recently, the investigators created a novel murine model. This model mimics human HCC initiation and
progression, and reflects typical features of human HCC including tumor-induced immunotolerance. Using this
model, they have first demonstrated that FDA-approved chemotherapeutic agent, sunitinib, prevents tumor
antigen-specific immunotolerance and allows effective immunotherapy resulting in regression of established
tumors in HCC, which is mechanistically associated with suppression of Tregs. By using nanotechnology to
develop nanoliposome-loaded C6-ceramide (LipC6), they demonstrated that LipC6 not only exerts tumoricidal
effect but also prevents tumor-induced immunotolerance by modulating tumor-associated macrophages (TAMs).
They have also found a critical role of immune checkpoints in HCC-induced profound immunosuppression, and
demonstrated that Ab-mediated blockade of PD-1 has a significant immunotherapeutic effect in the experimental-
HCC treatment. In addition, the investigators have successfully modified a human cardiac RFA generator, and
they are now able to conduct HCC tumor ablations in this novel murine model. The overall objective of the
proposed study is to develop and define the mechanisms of RFA-integrated chemo-immunotherapy against
HCC. They will achieve this goal via two specific aims: 1) Determine the therapeutic antitumor immune response
and elucidate the underl...

## Key facts

- **NIH application ID:** 9832135
- **Project number:** 5I01BX004065-02
- **Recipient organization:** HARRY S. TRUMAN MEMORIAL VA HOSPITAL
- **Principal Investigator:** Eric T. Kimchi
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9832135

## Citation

> US National Institutes of Health, RePORTER application 9832135, Building a New Therapeutic Paradigm for Hepatocellular Cancer by Dissecting the Interaction between Radiofrequency Ablation, Chemotherapy, and Immunotherapy (5I01BX004065-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9832135. Licensed CC0.

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