| Project/Area Number |
18H02876
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Review Section |
Basic Section 55020:Digestive surgery-related
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| Research Institution | Hokkaido University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
七戸 俊明 北海道大学, 医学研究院, 准教授 (70374353)
土川 貴裕 北海道大学, 大学病院, 講師 (50507572)
中村 透 北海道大学, 医学研究院, 助教 (70645796)
平岡 圭 北海道大学, 医学研究院, 客員研究員 (10719587)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥14,820,000 (Direct Cost: ¥11,400,000、Indirect Cost: ¥3,420,000)
Fiscal Year 2020: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2019: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2018: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
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| Keywords | 膵癌 / 新規遺伝子治療 / 腫瘍選択的増殖型レトロウイルスベクター / 膵癌新規治療 / K-RAS阻害治療 |
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| Outline of Final Research Achievements |
The prodrug activator gene therapy with Toca511, a tumor-selective retroviral replicating vector encoding an optimized yeast cytosine deaminase (yCD), is a strategy under clinical evaluation for various malignancies. Toca511 exerts direct anti-tumor effects through intratumoral conversion of the prodrug 5-fluorocytosine (5-FC) to the active drug 5-fluorouracil (5-FU) by its encoded yCD, and induce anti-tumor immunity by eliminating immunosuppressive cells. Toca511/5-FC treatment in immunocompetent bilateral subcutaneous Pan02 pancreatic ductal adenocarcinoma (PDAC) tumor models were evaluated. The CTL assays and in vivo therapeutic efficacy showed significant regression after 5-FC treatment in Toca511-transduced tumors compared to untransduced control. Furthermore, CD8+ T cells isolated from Toca511/5-FC treated mice showed higher cytotoxicity against Pan02 cells than controls, indicating that has potential to induce anti-tumor immune responses in the PDAC.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究結果で最も重要な点は、遺伝子治療の抗腫瘍免疫応答を介した治療効果は、転移先を想定した対側腫瘍（直接遺伝子治療を行っていない部位）にも効果を発揮するという点である。さらにプロドラッグ投与で膵癌細胞の抗PD-1の発現は高くなり、抗PD-1抗体併用で遺伝子治療の効果はさらに増強された。この治療効果はCD8+ T cellあるいはCD4+ T cellを抑制することで消退し、作用機序としてT cellが重要な役割を果たすことが明らかとなった。既存の化学療法併用における問題点などさらなる課題も示された。効果的な治療法のない転移性膵癌に対し、新規治療法の基盤を提示できた点で意義は大きい。
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