Development of novel anti-leukemia immunotherapy using neo-antigen specific CD4 helper T cells

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K08361
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Mie University
• Principal Investigator: Fujiwara Hiroshi 三重大学, 医学系研究科, 産学官連携講座准教授 (20398291)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: ネオアンチゲン / 遺伝子改変ヘルパーT細胞 / 骨髄性白血病 / 細胞免疫療法 / 白血病幹細胞

Outline of Final Research Achievements

For the treatment of refractory acute myeloid leukemia (rAML), a currently unmet need, we have been studying the capability of novel adoptive cellular immunotherapy using driver mutation-coded neoantigen reactive T cell receptor (TCR) gene-modified T cells (TCR-T). As a model for driver mutation-coded neoantigen, we chose HTLV-1 p40 Tax, the extrinsic causative factor for adult T-cell leukemia (ATL). We newly achieved HLA-A24 and -A2 restricted TCR αβ genes with high affinities from ATL patients, established TCR gene-modified T cells, and subsequently assessed the capability of this TCR-T therapy. As to development of strategy for neoantigen screening in cancer cells and generation of neoantigen-reactive TCR-T cells using TCR-αβ genes from tumor infiltrating lymphocytes (TIL), instead of rAML, we started to employ cancerous tissues from colon cancer patients, because of its abundance in mutations. Taking above, we are currently expanding this strategy to rAML and other cancers.

Free Research Field

血液内科学

Academic Significance and Societal Importance of the Research Achievements

がん細胞特有のネオアンチゲンを認識するT細胞療法は、従来のがん抗原特異的T細胞療法が抱える問題点である正常組織に対するon-target/off-tumor有害事象を解決できる可能性が高い。一方で、がん細胞が持つ遺伝子変異からネオアンチゲンを同定し、かつそれを特異的に認識するTCR遺伝子を腫瘍浸潤Tリンパ球から得て、治療用TCR遺伝子導入T細胞を作製するまでには膨大な作業を要しボトルネックとなっている。この行程を確立出来たことは、今後細胞製剤のみならずがんワクチンの臨床応用の可能性も高める社会的意義がある。