Next generation CAR-T cell therapy considering metabolism of tumor cells and CAR-T cells

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K07751
• 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: Mie University
• Principal Investigator: MIWA Hiroshi 三重大学, 医学系研究科, 産学官連携講座准教授 (00209967)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: CAR-T細胞 / エネルギー代謝

Outline of Final Research Achievements

We aimed to improve the efficacy of CAR-T cell therapy by understanding the energy metabolism of CAR-T cells in this study. We demonstrated that zG CAR-T cell, comprising GITR (Glucocorticoid-induced TNF-related Protein) in cytoplasmic domain had less dependency on glycolysis, and relied more on fatty acid beta oxidation and oxidative phosphorylation in mitochondria than CAR-T cells having 28z or 4-1BB. Real-time cytotoxicity assay revealed that zG CD19 CAR-T cells killed target leukemia cell line (NALM6) more efficiently than 28z or 4-1BBz CD19 CAR-T cells (gammadelta CAR-T). Superior target-specific cytotoxicity of zG CAR-T cells might be associated with OXPHOS-dominant metabolic characteristics.

Free Research Field

腫瘍免疫　エネルギー代謝

Academic Significance and Societal Importance of the Research Achievements

近年、CAR-T細胞のエネルギー代謝、殊にミトコンドリアでの酸化的リン酸化が注目されている。本研究にてCARの細胞内ドメインの違いにより解糖優位、ミトコンドリアでの酸化的リン酸化優位を類別化することができ、標的細胞傷害活性との関連が示唆された。CAR-T細胞治療は従来治療に不応性の難治がんへの有効性が期待されているが、費用対効果の面で問題がある。代謝特性の理解により有効性の向上に資するものと考えられる。