Solid cancer treatment with CAR-T cells resistant to the immunosuppressive mechanism of cancer microenvironment

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K07167
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor therapeutics
• Research Institution: Mie University
• Principal Investigator: Wang linan 三重大学, 医学系研究科, 特任助教(研究担当) (00589484)
• Co-Investigator(Kenkyū-buntansha): 加藤 琢磨 三重大学, 医学系研究科, 准教授 (60224515)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: CAR / CEA / GITR

Outline of Final Research Achievements

In our previous studies, using tumor bearing CEA-Tg mouse that physiologically express CEA in a manner like human, we have demonstrated: CEA-specific CAR-based adoptive T cell therapy may be effective for patients with solid tumors, but associates with symptom of cytokine release syndrome that leads anorexia. But administration of anti-IL-6R antibody successfully controlled cytokine releasing syndrome-like symptoms. Taken as a whole, these results suggest that CEA-specific CAR-based adoptive T cell therapy may be effective for patients with CEA+ solid tumors.To further augment the efficacy of CAR-T cell therapy against solid tumors, the immunosuppression should be overcome.
In the present study, we have developed a CAR consisting of a scFv specific to CEA in the ectodomain and CD3zeta and GITR signaling endodomain (CEA-zG.CAR). To further augment the efficacy of CAR-T cell therapy against solid tumors, the immunosuppression should be overcome.

Free Research Field

腫瘍免疫細胞治療学

Academic Significance and Societal Importance of the Research Achievements

本研究では、前述のがん微小環境における免疫抑制シグナルに抵抗性のGITRシグナル伝達ドメインを搭載したCEA特異的 CAR(zG型-CAR)導入T細胞の固形がんに対する有効性と優位性を、SHP2の脱リン酸化作用により失活する28z型CARとの比較により明らかにする。これにより、固形がんに特有ながん微小環境における免疫抑制機構を回避できるCAT-Tによる細胞輸注療法の開発を目指す。