Development of TCR gene therapy with allogeneic T cells deficient in endogenous TCR and MHC class I molecules

2023 Fiscal Year Final Research Report

• Project/Area Number: 19K23919
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0901:Oncology and related fields
• Research Institution: Nagasaki University
• Principal Investigator: Okada Satomi 長崎大学, 医歯薬学総合研究科(医学系), 客員研究員 (40849501)
• Project Period (FY): 2019-08-30 – 2024-03-31
• Keywords: 免疫療法 / 輸注療法 / 非自己リンパ球

Outline of Final Research Achievements

Adoptive immunotherapy using genetically engineered patient-derived lymphocytes to express tumor-reactive receptors is a promising treatment for malignancy. However, utilization of autologous T cells in this therapy limits the quality of gene-engineered T cells, thereby inhibiting the timely infusion of the cells into the patients. In this study, we evaluated the anti-tumor efficacy and the potential to induce graft-versus-host disease (GVHD) in T cell receptor (TCR) gene- engineered allogeneic T cells that downregulate the endogenous TCR and HLA class I molecules. We transduced human lymphocytes with a high-affinity TCR specific to the cancer/testis antigen NY-ESO-1, using a novel retrovirus vector with siRNAs specific to the endogenous TCR and lentivirus-based CRISPR/Cas9 system targeting β-2 microglobulin. In non-obese diabetic/SCID/γcnull mice, TCR gene-transduced T cells induced tumor regression without development of GVHD.

Free Research Field

消化器外科学

Academic Significance and Societal Importance of the Research Achievements

腫瘍を認識する受容体を遺伝子導入したＴ細胞の輸注療法は、悪性腫瘍に対する治療法として期待されている。しかしながら、自己細胞を用いた治療は品質の制限を受け、また投与までに長期間を要するため、有効性と汎用性を阻んでいる。本研究では、より効果的で汎用性の高いT細胞療法の開発を目指すため、非自己T細胞を用いた受容体改変T細胞療法に着目した。非自己T細胞を用いる際に“宿主組織傷害”と“輸注細胞の拒絶”が克服すべき課題であり、内因性TCR発現の抑制とMHC発現の抑制を行い、抗腫瘍効果を確認することができ、非自己T細胞による輸注療法の可能性を明らかにした。