Rapid CAR screening and circRNA-driven CAR-NK cells for persistent shed-resistant immunotherapy - PubMed
3 hours ago
- #circRNA engineering
- #CAR-NK cells
- #shed-resistant immunotherapy
- The study addresses two major challenges in CAR-based immunotherapy for solid tumors: the 'decoy effect' from shedding antigens and limited persistence of immune effectors in the tumor microenvironment.
- A rapid functional screening platform in human primary NK cells identified a novel scFv, CLMS10, which targets a membrane-proximal epitope overlapping the proteolytic cleavage site to evade inhibition by soluble mesothelin.
- CircRNA-mediated CAR expression, when co-delivered with IL-21, enhances stability and reduces CAR downregulation against continuous antigen shedding induced by cancer-associated fibroblasts.
- In an in vivo metastatic pancreatic cancer model, IL-21-augmented circCAR-MS10-NK cells showed potency similar to lentivirally engineered CAR-NK cells, with improved manufacturability.
- The research establishes a paradigm for creating shed-resistant CAR therapeutics through epitope-specific functional selection and enhanced RNA stability, supported by patents and funding from Korean institutions.