# Designer Cytokine Therapy of Hepatocellular Carcinoma

> **NIH NIH P01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2024 · $596,066

## Abstract

PROJECT 4: SUMMARY
Innovative therapeutic strategies are warranted to treat hepatocellular carcinoma (HCC), which is one of the
most common malignancies worldwide with current approaches being inadequate in accomplishing the
ultimate goal of curing this aggressive cancer. The focus of our project is to address this need and develop
improved molecular medicine(s) that selectively and specifically suppress primary liver tumor(s) and stimulate
enhanced immune responses to eliminate distant metastatic tumors. MDA-7/IL-24, a unique therapeutic
cytokine (secreted protein therapeutic) discovered in our laboratory, displays multifaceted anti-tumor properties
and confirmed safety and efficacy in a Phase I clinical trial in patients with advanced cancers following direct
administration in a replication-incompetent adenovirus (Ad.5-mda-7). Mechanism of action studies indicate that
MDA-7/IL-24 has profound anti-cancer activity, which occurs by direct induction of apoptosis and toxic
autophagy, inhibition of angiogenesis, enhanced recognition of cancer cells by the immune system, potent
“bystander” anti-tumor activity affecting both primary and metastatic cancers, and synergy with conventional
therapies (including radiation, chemotherapy, antibody-based therapy, and immunotherapy). Using a genetic
engineering strategy, we developed and provide proof-of-principle that the next generation of MDA-7/IL-24,
M7S/IL-24S, is superior in comparison with wild-type protein. In Aim 1, we engineered a fusion protein (IL-
24S/IL-15) with IL-24S and IL-15 to create an immuno-enhancing Fusion Superkine, FSK. Both IL-24S and IL-
24S/IL-15 will be incorporated in a cancer-selective conditionally replication-competent cancer terminator virus
(CTV) that is predicted to have superior anti-cancer attributes. In Aim 2, we will examine the efficacy of natural
killer (NK) cells expressing our modified/Fusion Superkine. Experiments will evaluate the feasibility of cell-
based therapies of HCC using these designer cytokine proteins in a single moiety, IL-24S/IL-15, which will elicit
both tumor-killing and immune modulatory effects along with NK-mediated cytotoxicity. In Aim 3, to accurately
target and deliver therapeutic payloads to the liver, we will use a novel state-of-the-art delivery strategy that
involves temporarily and non-invasively altering permeability of the liver using empty microbubbles (MBs) and
focused ultrasound (FUS) and then delivering the therapeutic in a second MB and releasing it in the liver with
FUS, i.e., the focused ultrasound double microbubble delivery (FUS-DMB) approach. Once the parameters for
efficient delivery of viruses to the liver are optimized, we will evaluate the activity of our therapeutics to treat
HCC. To improve activity of our CTV expressing FSK, a combinatorial regimen will be established with
Standard of Care or investigational drugs using multiple authentic HCC pre-clinical animal models. Successful
completion of the goals of our research o...

## Key facts

- **NIH application ID:** 10849091
- **Project number:** 1P01CA275740-01A1
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** PAUL B FISHER
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $596,066
- **Award type:** 1
- **Project period:** 2024-08-08 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10849091

## Citation

> US National Institutes of Health, RePORTER application 10849091, Designer Cytokine Therapy of Hepatocellular Carcinoma (1P01CA275740-01A1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10849091. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*