Development of CAR-T cell therapy for pediatric solid malignancy using advantages of induced pluripotent stem cells

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K16869
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Tokyo Medical University
• Principal Investigator: Watanabe Noriko 東京医科大学, 医学部, 講師 (50526176)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: CD99 / CAR / iPS細胞 / T細胞分化 / 小児悪性固形腫瘍

Outline of Final Research Achievements

The purpose of this study was to create a research system for a novel CAR-T therapy targeting CD99, which is frequently expressed in pediatric malignant solid tumors, using human iPS cells as a platform with excellent genetic manipulation properties. Anti-CD99 CARs were introduced into human iPS cells established from donor blood T cells, after that, induced into T cells. However, as strong expression of CD99 was observed in induced T cells, differentiation was performed after knockdown of CD99, but the differentiation efficiency decreased and CD99, which was supposed to be suppressed, was gradually expressed. Furthermore, during the research process, the affinity of the anti-CD99 CAR to CD99 could not be confirmed, and it was found that there was a problem with the three-dimensional structure of anti-CD99 scFv. We attempted to improve the structure, but were unable to make improvements.

Free Research Field

人体病理学

Academic Significance and Societal Importance of the Research Achievements

昨今のがん免疫療法の隆盛は、免疫チェックポイント阻害薬ならびにCAR-T療法の成功に拠るところが大きい。本研究は、CD99を標的とする今までにないCAR-T療法の開発を最終目標として、そのための実験システムを構築することを目的とした。CD99は小児の悪性固形腫瘍の3割程度に発現がみられる膜糖蛋白であり、標的分子として相応しいものと考えたが、当研究室で作製した抗CD99CARは、立体構造の問題点を克服することが出来ず、目的とした実験システムの構築に至ることは出来なかった。