2020 Fiscal Year Final Research Report

Retroviral replicating vector mediated gene therapy activates anti-tumor immune responses in an immunocompetent pancreatic cancer model

Research Project

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Project/Area Number	18H02876
Research Category	Grant-in-Aid for Scientific Research (B)
Allocation Type	Single-year Grants
Section	一般
Review Section	Basic Section 55020:Digestive surgery-related
Research Institution	Hokkaido University
Principal Investigator	Hirano Satoshi 北海道大学, 医学研究院, 教授 (50322813)
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)
Project Period (FY)	2018-04-01 – 2021-03-31
Keywords	膵癌 / 新規遺伝子治療
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.
Free Research Field	消化器外科
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。