The efficacy and safety of iPSC-derived CART therapy for small cell lung cancer

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K07781
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Juntendo University
• Principal Investigator: Ando Miki 順天堂大学, 医学部, 教授 (10424251)
• Co-Investigator(Kenkyū-buntansha): 安藤 純 順天堂大学, 医学部, 教授 (60348943)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: キメラ抗原受容体T細胞 / 小細胞肺がん / GD2-CAR / T-iPSC

Outline of Final Research Achievements

We have reported that iPSC-derived dual-antigen receptor rejuvenated T cells (rejTs) can target CD19 antigen via chimeric antigen receptor (CAR) and Epstein-Barr LMP2 antigen via native TCR, resulting in robust anti-tumor effect against EBV-associated lymphoma (Harada et al., Molecular Therapy, 2021). Applying this strategy to GD2 positive refractory tumors, we generated iPSC-derived GD2-CAR-rejTs and examined the efficacy and safety against GD2-positive small cell lung cancer (SCLC). Peripheral blood-derived GD2-CARTs did not show cytotoxicity against SCLC cell lines, whereas GD2-CAR-rejTs showed much stronger cytotoxicity against SCLC cell lines than that of peripheral blood-derived GD2-CARTs in vitro. Furthermore, GD2-CAR-rejTs successfully suppressed tumor growth in vivo compared to untreated mice. This approach would be a promising therapy for refractory SCLC.

Free Research Field

血液腫瘍学, キメラ抗原受容体T細胞療法, 遺伝子細胞療法、再生医学

Academic Significance and Societal Importance of the Research Achievements

小細胞肺がんは肺がんの中で最も進行が速く、多くの患者は再発し治療抵抗性を示す。5年生存率は７％以下と極めて予後不良にも関わらず、新規治療開発から長らく取り残されてきた。本研究では小細胞肺がんの多くが細胞表面にGD2を発現することに着目し、iPSCにGD2-CARを遺伝子導入後GD2-CARTを分化誘導し、小細胞肺がんに強力な治療となりうるか検証した。末梢血GD2-CARTは小細胞肺がんに細胞傷害活性を示さなかったが、iPSC由来GD2-CARTは強い細胞傷害活性を示した。小細胞肺がんに対する新規治療となりうる有望な結果であり、その抗腫瘍効果の差について解析することも学問的に重要と考える。