研究テーマResearch theme

Development of CAR-T cells specifically targeting shared-neoantigen/MHC complex

研究内容の概要Overview

Mutations in the RAS oncogene frequently occur in a variety of cancers, and approaches to target these mutations have been the subject of intense research for decades. The protein encoded by the mutated RAS gene is an intracellular protein that cannot be recognized by conventional CAR-T cells. However, intracellular proteins are processed by intracellular proteolytic machinery to generate peptides that can be presented on the cell surface as peptide-HLA (pHLA) complexes by human leukocyte antigen (HLA) molecules. We plan to utilize this property to construct novel TCR-like CAR-T cells that can recognize mutated RAS oncogenes. Firstly, we are identifying specific antibodies that can recognize mutated KRAS-derived peptide/HLA complex by screening a human scFv phage display library. Secondary, we are incorporating these antibodies as recognition domain of CAR construct, and investigating whether these CAR-T cells specifically recognize tumor cells expressing KRAS mutations.

研究成果をどのように社会に役立てるか
（還元の構想）Giving back to society

Cancer is a global public health problem and has been one of the most common diseases with the highest mortality rate in the world. In recent years, tumor immunotherapy has attracted great attention. Compared with traditional cancer treatment methods, tumor immunotherapy has the advantages of strong specificity, immune memory, and killing effect against primary and metastatic tumors. Indeed, tumor immunotherapy has become the fourth pillar of anti-cancer therapy, together with chemotherapy, surgery, and radiation therapy. On the other hand, RAS is the most frequently mutated oncogene in human cancers, accounting for approximately 30% of mutations in all human cancers. However, it is still challenging to target them with low molecular compounds. We think that KRAS-specific CAR-T cells could open opportunities for developing novel cancer treatments.

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