Professor Eunsung Jun’s Research Team at Asan Medical Center Develops and Applies CAR NK Technology to Eliminate Cancer Cells Even in Immunosuppressive Solid Tumor Environments

Single Process Gene Editing System Enabling Simultaneous Knockout and Knock in Enhances Clinical Applicability

“Anticancer Efficacy Validated Using Organoid Models… Potential Confirmed for Application Beyond Pancreatic Cancer to Solid Tumor Patients”

▲ Professor Eunsung Jun of the Biomedical Research Center at Asan Medical Center

Pancreatic ductal adenocarcinoma, the most common type of pancreatic cancer, is often diagnosed at an advanced stage and shows limited response to conventional treatments, resulting in a five year survival rate of only about 13%. In solid tumors such as pancreatic cancer, the fibrotic tumor microenvironment suppresses immune cell function, which has limited the effectiveness of immunotherapy.

Recently, a Korean research team successfully developed an immune cell therapy using gene editing technology that maintains its anticancer activity even in immunosuppressive tumor environments.

A joint research team led by Professor Eunsung Jun of the Biomedical Research Center at Asan Medical Center, Dr. Mihue Jang of the Korea Institute of Science and Technology, and Professor Daechan Park of the Department of Molecular Science and Technology at Ajou University recently announced that they have developed chimeric antigen receptor natural killer cells, or CAR NK cells. These cells block transforming growth factor beta TGF β signaling, which inhibits immune cell infiltration, while simultaneously targeting and eliminating cancer cells. The team validated the therapy’s anticancer efficacy through experiments using pancreatic cancer derived organoid models and animal studies.

This study is significant in that it enhances clinical applicability and establishes a foundation for large scale production by developing CAR NK cells using a single process gene editing platform capable of simultaneously performing gene knockout and knock in. The technology is expected to open new possibilities not only for pancreatic cancer but also for the development of treatments targeting solid tumors that have been difficult to treat with immunotherapy.

Natural killer NK cells are key components of the innate immune system and can directly eliminate cancer cells or damaged cells without prior antigen recognition. In particular, CAR NK cells equipped with chimeric antigen receptors are gaining attention as next generation immuno oncology therapies, as they carry a lower risk of side effects such as cytokine release syndrome and offer advantages in large scale manufacturing compared to conventional immunotherapies.

However, in solid tumors such as pancreatic cancer, transforming growth factor beta TGF β present in the tumor microenvironment is known to strongly suppress NK cell function. This factor reduces cytotoxicity and the expression of activating receptors, while also impairing cellular energy metabolism, ultimately weakening the overall anticancer activity of immune cells.

Conventional CAR NK therapies have shown limitations in maintaining persistence and functionality under such conditions. In addition, the complex manufacturing process, which requires separate steps for gene knockout and knock in, has posed a major obstacle to large scale production and clinical translation.

To address these challenges, the research team employed CRISPR Cas9 based gene editing technology to simultaneously remove the receptor responsible for transmitting TGF beta signaling in NK cells while inserting a chimeric antigen receptor that recognizes mesothelin, a target protein expressed in pancreatic cancer.

In this process, the team established a non-viral system using electroporation to perform gene knockout and knock in in a single step, thereby improving manufacturing efficiency and enhancing clinical applicability. In addition, the use of the anti-inflammatory steroid dexamethasone during gene editing increased gene insertion efficiency and further strengthened cellular function.

The newly developed CAR NK cells demonstrated enhanced cancer cell killing activity. Notably, when combined with dexamethasone, the cells showed increased proliferative capacity and higher expression of key activating receptors. In addition, activation of cellular energy metabolism was observed, indicating an improved ability to generate energy and sustain functionality over an extended period.

The research team also evaluated the therapeutic efficacy of the CAR NK cells using organoid models that reflect the tumor characteristics of pancreatic cancer patients. The results showed that the CAR NK cells achieved a cancer cell killing rate of 55.4% even in an immunosuppressive environment with TGF beta present, which increased to 68.3% when combined with dexamethasone.

The anticancer efficacy was also confirmed in animal studies. In a pancreatic ductal adenocarcinoma xenograft model, administration of CAR NK cells effectively suppressed tumor growth. Notably, the strongest antitumor effect was observed when combined with dexamethasone.

Professor Eunsung Jun of the Biomedical Research Center at Asan Medical Center said, “In this study, we conducted a range of efficacy evaluations of CAR NK cell therapy using organoid models derived from tumor tissues of patients with pancreatic cancer. The findings are clinically meaningful in that they demonstrate the potential for this approach to be developed into a treatment strategy applicable to patients with solid tumors.”

Dr. Mihue Jang of the Korea Institute of Science and Technology said, “The CAR NK cells developed in this study possess resistance to immunosuppression and strong tumor specificity, enabling them to selectively target and eliminate cancer cells even within the tumor microenvironment. We expect this research to serve as a foundation for expanding treatment strategies that could improve survival rates not only for pancreatic cancer but also for patients with various solid tumors.”

This study was supported by the Bio & Medical Technology Development Program, the Mid Career Researcher Program, and the Global Leading Research Center Program G LAMP. The findings were published in the latest issue of Theranostics, a prestigious international journal in the field of medical research with an impact factor of 13.3.