Development of novel immune cell therapy combined with immune checkpoint inhibitors

• Project/Area Number: 26460914
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General internal medicine(including psychosomatic medicine)
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: Ishikawa Takeshi 京都府立医科大学, 医学(系)研究科(研究院), 講師 (90372846)
• Co-Investigator(Kenkyū-buntansha): 岡山 哲也 京都府立医科大学, 医学(系)研究科(研究院), 助教 (30636535) ; 坂元 直行 公益財団法人ルイ・パストゥール医学研究センター, その他部局等, 研究員(移行) (40547981)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 免疫チェックポイント阻害剤 / がん免疫療法 / 細胞移入療法

Outline of Final Research Achievements

Although immune checkpoint inhibitors (ICI) improve clinical outcomes in numerous malignancies, the achievement of durable response is rare in many cancers and the anti-tumor effects of ICI cannot be expected in patients with an absence of CTLs in tumors. Development of new multidisciplinary treatment using immunotherapies and conventional treatment including chemotherapy is necessary for improving treatment outcomes of ICI. This study indicated that adoptive T-cell therapy combined with ICI potentiate the antitumor effects, partially resulting from Th1 polarization and the reduction of the number of Foxp3(+) cells in the tumor. In the study on the effect of anticancer drugs on immune checkpoint molecules, we observed that PD-L1 surface protein expression was enhanced, when pancreatic cancer cell lines were stimulated by anticancer drugs. We believe that our results of the present study will contribute to the development of new immune-based combination therapies.

Research Products

• [Journal Article] The JAK/STAT pathway is involved in the upregulation of PD-L1 expression in pancreatic cancer cell lines. (2017)
  • Author(s): Doi T, Ishikawa T, Okayama T, Oka K, Mizushima K, Yasuda T, Sakamoto N, Katada K, Kamada K, Uchiyama K, Handa O, Takagi T, Naito Y, Itoh Y
  • Journal Title: Oncology report Volume: 37 Issue: 3 Pages: 1545-1554
  • DOI: 10.3892/or.2017.5399
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Cytotoxic T lymphocyte-associated antigen 4 inhibition increases the antitumor activity of adoptive T-cell therapy when carried out with naïve rather than differentiated T cells. (2015)
  • Author(s): Ishikawa T, Adachi S, Okayama T, Kokura S
  • Journal Title: Oncol Rep. Volume: 33(5) Issue: 5 Pages: 2545-2552
  • DOI: 10.3892/or.2015.3815
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Tumor inoculation site affects the development of cancer cachexia and muscle wasting. (2015)
  • Author(s): Matsuyama T, Ishikawa T, Okayama T, Oka K, Adachi S, Mizushima K, Kimura R, Okajima M, Sakai H, Sakamoto N, Katada K, Kamada K, Uchiyama K, Handa O, Takagi T, Kokura S, Naito Y, Itoh Y.
  • Journal Title: Int J Cancer. Volume: Dec 1;137(11) Issue: 11 Pages: 2558-65
  • DOI: 10.1002/ijc.29620
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. (2015)
  • Author(s): Sakamoto N, Ishikawa T, Kokura S, Okayama T, Oka K, Ideno M, Sakai F, Kato A, Tanabe M, Enoki T, Mineno J, Naito Y, Itoh Y, Yoshikawa T.
  • Journal Title: J Transl Med. Volume: Aug 25;13 Issue: 1 Pages: 277-277
  • DOI: 10.1186/s12967-015-0632-8
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] 抗癌刺激はJAK/STAT経路を介し、膵癌細胞株のPD-L1発現を亢進する (2016)
  • Author(s): 土井俊文、石川剛、岡山哲也、他
  • Organizer: 第20回日本がん免疫学会総会
  • Place of Presentation: 大阪
  • Year and Date: 2016-07-27
• [Presentation] The expression of PD-L1 on human and murine pancreatic ductal adenocarcinoma is enhanced by anticancer agents via the JAK/STAT pathway. (2016)
  • Author(s): Doi T, Ishikawa T, Yasuda T, et al
  • Organizer: the 107th Annual Meeting of the American Association for Cancer Research
  • Place of Presentation: New Orleans, Louisiana, USA
  • Year and Date: 2016-04-16
  • Int'l Joint Research
• [Presentation] 抗癌剤は膵癌細胞株のPD-L1発現を増強し、温熱処理は抗癌剤誘導PD-L1発現を抑制する (2015)
  • Author(s): 土井俊文、石川剛、岡要、安田知代、岡山哲也、坂元直行、鎌田和浩、堅田和弘、内山和彦、半田修、高木智久、内藤裕二、伊藤義人
  • Organizer: 第28回日本バイオセラピィ学会学術集会総会
  • Place of Presentation: 川越
  • Year and Date: 2015-12-03
• [Presentation] The influence of anticancer agents and heat treatment on PD-L1 expression on pancreatic cancer cell lines (2015)
  • Author(s): 岡要、土井俊文、石川剛、岡山哲也、安田知代、坂元直行、堅田和弘、鎌田和浩、内山和彦、半田修、高木智久、内藤裕二、伊藤義人
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-09
• [Presentation] A novel expansion method for functional natural killer cells and its clinical applicatio. (2015)
  • Author(s): Takeshi Ishikawa, Naoyuki Sakamoto, Tetsuya Okayama , Satoshi Kokura, Mitsuko Ideno, Akiko Kato, Tatsuji Enoki,, Masanari Kitagawa, Junichi Mineno, Tomoyo Yasuda, Toshifumi Doi, Yuji Naito, Yoshito Itoh, Toshikazu Yoshikawa
  • Organizer: 106th Annual Meeting of the American Association for Cancer Research
  • Place of Presentation: Philadelphia
  • Year and Date: 2015-04-21
  • Int'l Joint Research
• [Presentation] The influence of anticancer agents and hyperthermia on PD-L1 expression on human and murine pancreatic cancer cell lines. (2015)
  • Author(s): Toshifumi Doi, Tetsuya Okayama, Takeshi Ishikawa, Kaname Oka, Naoyuki Sakamoto, Yuji Naito, Yoshito Itoh
  • Organizer: 106th Annual Meeting of the American Association for Cancer Research
  • Place of Presentation: Philadelphia
  • Year and Date: 2015-04-20
  • Int'l Joint Research
• [Presentation] Elevated levels of plasma VEGF associated with the attenuation of whole blood IFN-γ production and QOL impairment in patients with advanced gastric cancer. (2015)
  • Author(s): Naoyuki Sakamoto, Takeshi Ishikawa, Toshihumi Doi, Tetsuya Okayama, Hideyuki Konishi, Satoshi Kokura, Yuji Naito, Yoshito Ito, Toshikazu Yoshikawa
  • Organizer: 106th Annual Meeting of the American Association for Cancer Research
  • Place of Presentation: Philadelphia
  • Year and Date: 2015-04-20
  • Int'l Joint Research
• [Presentation] NK細胞を用いた胃癌に対するTrastuzumabの抗腫瘍効果増強についての検討 (2014)
  • Author(s): 岡山 哲也, 石川 剛, 坂元 直行, 古倉 聡, 出野 美津子, 加藤 彰子, 榎 竜嗣, 峰野 純一, 吉田 直久, 鎌田 和浩, 堅田 和弘, 内山 和彦, 半田 修, 高木 智久, 小西 英幸, 八木 信明, 内藤 裕二, 吉川 敏一, 伊藤 義人
  • Organizer: 第54回日本消化器病学会大会
  • Place of Presentation: 神戸
  • Year and Date: 2014-10-24
• [Presentation] CTLA-4阻害薬は分化型よりも未分化型T細胞を用いた養子免疫療法との併用においてより強い効果を発揮する (2014)
  • Author(s): 石川 剛、足立 聡子、岡山 哲也、岡 要、土井 俊文、坂元 直行、鎌田 和浩、内山 和彦、半田 修、高木 智久、古倉 聡、内藤 裕二、伊藤 義人
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25
• [Presentation] 行・再発消化器がんを対象とした新規培養法を用いた高純度NK細胞療法の第I相臨床試 (2014)
  • Author(s): 坂元 直行、石川 剛、岡山 哲也、出野 美津子、榎 竜嗣、峰野 純一、古倉 聡、内藤 裕二、伊藤 義人、吉川 敏一
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-09-25
• [Presentation] Advantages and clinical application of fibronectin CH296-stimulated T cells in cancer immunotherapy (2014)
  • Author(s): Ishikawa T, Kokura S, Okayama T, Sakamoto N, Ideno M, Muraki N, Kato A, Enoki T, Mineno J, Naito Y, Itoh Y, Yoshikawa T.
  • Organizer: 105th Annual Meeting of the American Association for Cancer Research
  • Place of Presentation: San Diego, CA
  • Year and Date: 2014-04-07
• [Presentation] High purity and activity NK cells therapy in patients with advanced gastrointestinal cancer: Phase I study (2014)
  • Author(s): Okayama T, Kokura S, Ishikawa T, Sakamoto N, Ideno M, Sakai F, Kato A, Enoki T, Mineno J, Konishi H, Naito Y, Itoh Y, Yoshikawa T.
  • Organizer: 105th Annual Meeting of the American Association for Cancer Research
  • Place of Presentation: San Diego, CA
  • Year and Date: 2014-04-07
• [Book] Hyperthermia Combined with Chemotherapy: Pancreatic Cancer. Hyperthermic Oncology from Bench to Bedside. (2016)
  • Author(s): Takeshi Ishikawa
  • Publisher: Springer