UCLA researchers in the School of Dentistry and Interventional Radiology have developed a groundbreaking curative treatment for hepatocellular carcinoma that combines locoregional therapy, such as ablation or catheter-based embolization, with targeted delivery of supercharged NK cells and CAR-NK or CAR-T cells, offering a highly effective approach that overcomes traditional limitations of immunotherapy while minimizing off-target toxicity.
BACKGROUND: Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, ranking as the fourth-leading cause of cancer-related deaths worldwide. While early- to intermediate-stage HCC is primarily treated with liver transplantation, surgical resection, or locoregional therapy, immunotherapy remains primarily reserved for advanced-stage cases. Ablation or catheter-based embolization of targeted HCC can modify the tumor microenvironment to promote CD8+ T cell infiltration, enhancing the efficacy of immunotherapy and creating a promising avenue for combining these approaches as a curative strategy for HCC. However, CD8+ T cell-based immunotherapy is limited by challenges such as T cell exhaustion and the sustained expression of inhibitory receptors. In contrast, natural killer (NK) cells, which are antigen-independent, can overcome these limitations but are often defective in HCC patients, and scaling functional NK cells to therapeutic levels is a significant challenge. This highlights the unmet need for an integrated treatment strategy that enhances NK cell functionality and scalability to improve outcomes for HCC patients.
INNOVATION: UCLA researchers led by Dr. Anahid Jewett have developed an exceptionally powerful curative treatment for HCC that combines supercharged NK (sNK) cells, CAR-NK or CAR-T cells, and locoregional therapy. These modified sNK cells can be rapidly expanded and demonstrate potent tumor-killing activity against various solid tumors, including oral squamous cell carcinoma and pancreatic adenocarcinoma. They secrete higher levels of IFN-γ, enhancing tumor cell death, tumor differentiation, and CD8+ T cell recruitment. By optimizing the viscosity of sNK cells, they can be efficiently delivered directly into the tumor microenvironment via intravascular catheters or percutaneous needles, eliminating off-target toxicity associated with systemic CAR-NK or CAR-T therapies.
POTENTIAL APPLICATIONS:
- Enhanced approaches to cancer immunotherapy
- Can be adapted to be used in conjunction with locoregional therapy
- Curative treatment for HCC
- Therapy for other solid tumors, including oral squamous cell carcinoma and pancreatic adenocarcinoma
ADVANTAGES:
- sNK cells can bypass the traditional limitations of NK cell or T cell immunotherapy.
- sNK cells can be rapidly expanded and exhibit potent tumor-killing activity across various solid tumors, while secreting high levels of IFN-γ to enhance tumor cell death, differentiation, and CD8+ T cell recruitment.
- The combination of sNK cells and locoregional therapy demonstrates highly effective and targeted killing of HCC cells.
- Catheter or needle delivery of sNK cells targets the tumor microenvironment directly, eliminating off-target toxicity and side effects seen with systemic CAR-T or CAR-NK therapies.
DEVELOPMENT-TO-DATE: Researchers have successfully demonstrated the efficacy of combining microwave ablation and sNK cell therapy in an in vivo mouse model study.
Related papers (from the inventors only):
Kaur K, Jewett A. Supercharged NK Cell-Based Immuotherapy in Humanized Bone Marrow Liver and Thymus (Hu-BLT) Mice Model of Oral, Pancreatic, Glioblastoma, Hepatic, Melanoma and Ovarian Cancers. Crit Rev Immunol. 2023;43(2):13-25. doi: 10.1615/CritRevImmunol.2023050618. PMID: 37938193.
Nguyen T, Chen PC, Pham J, Kaur K, Raman SS, Jewett A, Chiang J. Current and Future States of Natural Killer Cell-Based Immunotherapy in Hepatocellular Carcinoma. Crit Rev Immunol. 2024;44(5):71-85. doi: 10.1615/CritRevImmunol.2024052486. PMID: 38618730.
Chiang J, Chen PC, Pham J, Nguyen CQ, Kaur K, Raman SS, Jewett A. Characterizing hepatocellular carcinoma stem markers and their corresponding susceptibility to NK-cell based immunotherapy. Front Immunol. 2023 Oct 26;14:1284669. doi: 10.3389/fimmu.2023.1284669. PMID: 37954598; PMCID: PMC10637628.
KEYWORDS: Hepatocellular carcinoma, locoregional therapy, immunotherapy, liver cancer, natural killer cells, T cells, supercharged NK cells, curative cancer therapy, chimeric antigen receptor, ablation, intravascular catheters, catheter-based embolization, percutaneous needles, HCC, NK cells, sNK cells, CAR-NK cells, CAR-T cells