Seoul National University College of Medicine and KIST Overcome the Biggest Challenge in Solid Tumor Immunotherapy: "Antigen Shedding" [Reading Science]

Development of next-generation CAR-NK platform
Demonstrates efficacy in metastatic pancreatic cancer model, with improved manufacturability

A next-generation chimeric antigen receptor natural killer cell (CAR-NK) platform that can overcome “antigen shedding”—long considered the greatest challenge in solid tumor immunotherapy—has been developed by a team of researchers in Korea.

This new design principle enables evasion of the so-called “decoy effect,” in which cancer cells sever target antigens and release them into bodily fluids to mislead therapeutic cells. At the same time, it allows CAR-NK cells to sustain their cytotoxicity for a prolonged period within the tumor microenvironment. As a result, the platform is expected to provide a genuine breakthrough for CAR therapies targeting solid tumors.

Schematic of next-generation CAR-NK therapy development strategy. Using an mRNA-based platform that complements the existing lentivirus-based method, it is possible to evade the soluble MSLN secreted by cancer cells while rapidly selecting the most effective CAR (part 1). This is then produced as stable circular RNA to dramatically enhance anticancer efficacy and durability (part 2). Image and description provided by the research team.

On April 15, the research team led by Professor Lee Changhan at Seoul National University College of Medicine and Dr. Jang Mihui at the Korea Institute of Science and Technology (KIST) announced they had developed a shed-resistant mesothelin CAR-NK platform through a joint study with UCI Therapeutics in the United States.

The findings have been published in the international journal “Signal Transduction and Targeted Therapy.”

Mesothelin (MSLN) is highly expressed in solid tumors such as pancreatic cancer, ovarian cancer, and mesothelioma, making it a promising target. However, the antigen is easily shed, leading to increased levels of soluble mesothelin (solMSLN). This soluble form binds to the CAR on therapeutic cells before they can engage the actual tumor cells, significantly diminishing the efficacy of conventional CAR therapies.

New binding molecule overcomes decoy effect... Sustains cytotoxicity in tumor environment

The research team identified a novel single-chain variable fragment (scFv), CLMS10, through a rapid functional screening that directly compared candidates in primary human-derived natural killer (NK) cells. This binding molecule targets a region near the cancer cell membrane that overlaps with the antigen-shedding site, thereby reducing the phenomenon where soluble antigens intercept therapeutic cells first.

Image and description: Provided by the research team

By combining circular RNA (circRNA)-based CAR expression with simultaneous delivery of interleukin-21 (IL-21), the researchers greatly reduced both the decline in function and the decrease in CAR expression that typically occur after repeated attacks in the tumor microenvironment. Notably, even under conditions simulating the actual tumor environment—where cancer-associated fibroblasts (CAFs) secrete large amounts of soluble antigens—CAR-NK cells were able to stably eliminate cancer cells.

The key advantage is durability. While conventional lentivirus-based CAR-NK therapies demonstrate strong efficacy but are complex to manufacture, this new platform leverages circRNA to achieve both ease of manufacturing and scalability.

Proven in metastatic pancreatic cancer... A paradigm shift for solid tumor CAR therapy?

In animal models of metastatic pancreatic cancer, the IL-21 enhanced circCAR-MS10-NK cells demonstrated anticancer efficacy comparable to that of conventional lentivirus-based CAR-NK cells, while offering superior manufacturability.

This represents the first design strategy to simultaneously address both major bottlenecks in solid tumor CAR therapy: the decoy effect of soluble antigens and the lack of durability within the tumor microenvironment.

Professor Lee Changhan of Seoul National University College of Medicine and Dr. Jang Mihui of KIST stated, "We have concurrently overcome the antigen shedding problem, a repeated cause of failure in solid tumor therapy, through binding site design and the RNA platform. We expect this next-generation cell therapy platform can be extended not only to pancreatic cancer but also to various solid tumors expressing mesothelin."

This content was produced with the assistance of AI translation services.