Development of adoptive cell transfer using pancreatic cancer-specific genetically modified T cells combined with a desmoplasia-blocking peptide in pancreatic cancer

2020 Fiscal Year Final Research Report

• Project/Area Number: 17K09464
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Jikei University School of Medicine (2019-2020); Kyushu University (2017-2018)
• Principal Investigator: Murahashi Mutsunori (伊賀睦了) 東京慈恵会医科大学, 医学部, 准教授 (20422420)
• Co-Investigator(Kenkyū-buntansha): 大西 秀哉 九州大学, 医学研究院, 准教授 (30553276) ; 岸 裕幸 富山大学, 学術研究部医学系, 教授 (60186210)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Keywords: 膵癌 / 免疫治療 / 線維化

Outline of Final Research Achievements

We found that the anti-fibrosis peptide Patched 1 binding peptide reduces TGFβ1 production in cancer-related fibroblasts (CAFs) and increases HLA-class I expression in pancreatic cancer cells and IFNγ production in lymphocytes. We created a mouse treatment model in which immunodeficient mice were formed with a subcutaneous tumor mixed with a pancreatic cancer cell line and CAFs, and human lymphocytes, anti-PD-1 antibody, and Patched 1-binding peptide were administered. In the three-drug combination group, a significant decrease in tumor volume and an increase in the number of cancer-infiltrating CD3 + T lymphocytes were observed. These results indicate that, in addition to the direct antitumor effect of the Patched1-binding peptide, the increase in immune cells due to reduced fibrosis enhances the antitumor effect.

Free Research Field

腫瘍免疫学

Academic Significance and Societal Importance of the Research Achievements

膵癌の遺伝子異常に反応するTリンパ球の誘導は術後長期生存に貢献するとの報告があるが、線維成分を含む膵癌組織が免疫細胞のリクルートを阻害している可能性が指摘されており、我々は本研究においてその病態を証明した（Oyama Y, J Immunother. 2020）。この特徴的な病態を擬似した治療効果評価系の開発は、膵癌免疫療法開発を大きく前進させると考えられる。免疫細胞の抗腫瘍効果は三次元構造体での評価が必要であるが、実用的な治療評価系の開発が実現しないまま大きな課題であり続けている。この問題に対して、今後、我々は独自の細胞スフェロイド作製技術を応用して殺細胞効果評価系の臨床応用を目指していく。