Development of new immuno-cell therapy for the treatment of refractory malignant ascites and pleural effusion

• Project/Area Number: 19K09196
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Shiga University of Medical Science
• Principal Investigator: Kojima Masatsugu 滋賀医科大学, 医学部, 助教 (10452236)
• Co-Investigator(Kenkyū-buntansha): 村田 聡 滋賀医科大学, 医学部, 講師 (90239525) ; 下地 みゆき 滋賀医科大学, 医学部, 技術補佐員 (50796448) ; 目片 英治 滋賀医科大学, 医学部, 教授 (80314152) ; 谷 眞至 滋賀医科大学, 医学部, 教授 (60236677)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 胸膜・腹膜転移 / 癌性胸水・腹水 / がん抗原ペプチド / OX40補助刺激 / PD-1阻害薬 / がん抗原特異的CTL / 癌免疫細胞療法 / 免疫寛容 / 腹膜播種 / OX40 / 免疫チェックポイント阻害薬 / 免疫細胞治療 / 養子免疫 / CTL / 免疫チェックポイント阻害剤 / がん性腹水 / 腹膜播種性転移 / 難治性がん性腹水 / TAL / LAP吸着カラム / 抗OX40 抗体

Outline of Research at the Start

癌性腹水・胸水中の細胞傷害性T細胞（CTL）を含む豊富な免疫細胞（TAL）に着目し、免疫トレランス環境にあるTALから、トレランスに打ち勝つ癌抗原特異的CTLを樹立する事が本研究の目的である。高免疫原性のがん抗原：WT1やMUC-1タンパクを網羅するペプチドカクテルや、TGF-β陽性細胞除去カラム、T細胞補助刺激因子OX40 (CD134)、免疫チェックポイント阻害剤などを利用して、エフェクター機能が増強され、担癌患者体内でもCTL機能維持可能で、かつ、TAL由来の、HLAタイプによらず全ての患者に適用可能な、多種類の癌抗原特異的CTLを樹立したい。

Outline of Final Research Achievements

To establish a cancer antigen-specific CTL that overcomes immune tolerance using immune cells (TAL) in malignant ascites and pleural effusion, immunosuppressive cells were removed from TAL by (1) TGF-β positive cell removal column to prepare the immune environment. In this state, the cells were cultured under (2) cancer antigen peptide stimulation, (3) T cell co-stimulatory factor OX40 stimulation, and immune checkpoint PD-1 inhibition. As a result, HER2-specific CTL could be induced from TAL of HER2-specific immune-tolerant mice, and the antitumor effect on HER2-positive cells was confirmed. A TAL-derived CTL in the malignant ascites of a patient has been established, and the antitumor effect is being evaluated using a PDX mouse peritoneal metastasis model derived from the patient's cancer cells.

Academic Significance and Societal Importance of the Research Achievements

腹膜転移や胸膜転移による、難治性の癌性腹水・胸水で苦しむ患者は多いが、現医療では効果的な治療はなく、斬新な発想での治療開発研究が必要である。本研究により、免疫環境を整え、効果的に免疫作動薬等を使用すれば、免疫トラレンス環境にある癌性腹水中のリンパ球から、がん抗原特異的CTLが誘導可能なことが示唆された。このCTLは、癌性腹水・胸水へのCTL細胞治療として臨床応用できるだけでなく、その原因である腹膜転移や胸膜転移への治療展開に貢献できるであろう。

Research Products

• [Journal Article] Long-term prognosis of patients with cancer-related genes detected in postoperative peritoneal washings obtained during curative gastrectomy (2022)
  • Author(s): Takebayashi Katsushi、Murata Satoshi、Kodama Hirokazu、Kaida Sachiko、Yamaguchi Tsuyoshi、Ishikawa Ken、Shimoji Miyuki、Miyake Toru、Ueki Tomoyuki、Kojima Masatsugu、Iida Hiroya、Maehira Hiromitsu、Shimizu Tomoharu、Tani Masaji
  • Journal Title: European Journal of Surgical Oncology Volume: 48 Issue: 1 Pages: 177-182
  • DOI: 10.1016/j.ejso.2021.05.012
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Predictors and clinical impact of postoperative diarrhea after colorectal cancer surgery: a prospective, multicenter, observational study (SHISA-1602) (2022)
  • Author(s): Ohta Hiroyuki、Miyake Toru、Ueki Tomoyuki、Kojima Masatsugu、Kawasaki Masayasu、Tatsuta Takeshi、Iuchi Takekazu、Kamitani Sumihiro、Shimizu Tomoharu、Mekata Eiji、Tani Masaji
  • Journal Title: International Journal of Colorectal Disease Volume: 37 Issue: 3 Pages: 657-664
  • DOI: 10.1007/s00384-022-04097-8
  • NAID: 120007190901
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] INI1-negative colorectal undifferentiated carcinoma with rhabdoid features and postoperative rapidly growing liver metastases: a case report and review of the literature (2021)
  • Author(s): Kojima Masatsugu、Miyake Toru、Ueki Tomoyuki、Ohta Hiroyuki、Kushima Ryoji、Shiohara Masanori、Mizuta Hiroo、Iida Hiroya、Yamaguchi Tsuyoshi、Kaida Sachiko、Takebayashi Katsushi、Maehira Hiromitsu、Nishina Yusuke、Shimizu Tomoharu、Mekata Eiji、Tani Masaji
  • Journal Title: Surgical Case Reports Volume: 7 Issue: 1
  • DOI: 10.1186/s40792-021-01189-5
  • Peer Reviewed / Int'l Joint Research
• [Presentation] CD44+ cancer cells in the free peritoneal cavity and surgical manipulation as the cause of gastric cancer-derived peritoneal metastasis (2021)
  • Author(s): Andreas Michael Sihombing1, Satoshi Murata1,2, Miyuki Shimoji1, Sakura Nakao1, Katsushi Takebayashi1, Hirokazu Kodama1, Masatsugu Kojima1, Tomoyuki Ueki1, Naomi Kitamura3, Mina Kitamura1, Aya Tokuda1, Toru Miyake1, Eiji Mekata3, Masaji Tani1
  • Organizer: JCA-AACR
  • Int'l Joint Research
• [Presentation] Characterization of Tumor-associated lymphocytes (TAL) in malignant ascites of immune-tolerant mice (2021)
  • Author(s): Miyuki Shimoji 1), Satoshi Murata 2), Masatsugu Kojima 1), Mina Kitamura 1), Andreas Michael Sihombing 1), Sakura Nakao 1), Naomi Kitamura 3), Tomoyuki Ueki 1), Katsushi Takebayashi 1), Hirokazu Kodama 1), Aya Tokuda 1), Toru Miyake 1), Eiji Mekata 3), Masaji Tani 1)
  • Organizer: JCA-AACR
  • Int'l Joint Research
• [Presentation] Induction of tumor Ag-specific CTL using tumor-associated lymphocytes (TAL) in malignant ascites of immune-tolerant mice (2021)
  • Author(s): Satoshi Murata, Miyuki Shimoji, Masatsugu Kojima, Mina Kitamura, Andreas Michael Sihombing, Sakura Nakao, Naomi Kitamura, Tomoyuki Ueki, Katsushi Takebayashi, Hirokazu Kodama, Aya Tokuda, Toru Miyake, Eiji Mekata, Masaji Tani
  • Organizer: 第80回日本癌学会
• [Presentation] Crosstalk of microsomal glutathione transferase 1 (MGST1) and CD44 in T3M4 human pancreatic cancer cells on hyperthermic model (2021)
  • Author(s): Miyuki Shimoji1, Satoshi Murata1,2, Andreas Michael Sihombing1, Sakura Nakao1, Katsushi Takebayashi1, Hirokazu Kodama1, Masatsugu Kojima1, Tomoyuki Ueki1, Naomi Kitamura3, Mina Kitamura1, Aya Tokuda1, Toru Miyake1, Eiji Mekata3, Masaji Tani1
  • Organizer: 第80回日本癌学会
• [Presentation] Relationship between CD44-positive cancer stem-like cells and gastric cancer-derived peritoneal metastasis (2021)
  • Author(s): Andreas Michael Sihombing1, Satoshi Murata1,2, Miyuki Shimoji1, Sakura Nakao1, Katsushi Takebayashi1, Hirokazu Kodama1, Masatsugu Kojima1, Tomoyuki Ueki1, Naomi Kitamura3, Mina Kitamura1, Aya Tokuda1, Toru Miyake1, Eiji Mekata3, Masaji Tani1
  • Organizer: 第80回日本癌学会
• [Presentation] Overcoming immune tolerance to tumor antigens and inducing tumor antigen-specific CTLs by combined immunotherapy (2021)
  • Author(s): Sakura Nakao, Satoshi Murata, Miyuki Shimoji, Masatsugu Kojima, Mina Kitamura, Andreas Michael Sihombing, Naomi Kitamura, Tomoyuki Ueki, Katsushi Takebayashi, Hirokazu Kodama, Aya Tokuda, Toru Miyake, Eiji Mekata, Masaji Tani
  • Organizer: 第80回日本癌学会
• [Presentation] Tumor Ag-specific CTL generation from tumor-associated lymphocytes (TAL) in malignant ascites of peritoneal metastases (2020)
  • Author(s): Masatsugu Kojima, Satoshi Murata, Miyuki Shimoji, Andreas Michael Sihombing, Naomi Kitamura, Tomoyuki Ueki, Mina Kitamura, Katsushi Takebayashi, Hirokazu Kodama, Aya Tokuda, Toru Miyake, Eiji Mekata, Masaji Tani
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] CD44-enriched cancer stem-like cells as a source of peritoneal metastasis from gastric cancer (2020)
  • Author(s): Andreas Michael Sihombing, Satoshi Murata, Miyuki Shimoji, Katsushi Takebayashi, Hirokazu Kodama, Masatsugu Kojima, Tomoyuki Ueki, Naomi Kitamura, Mina Kitamura, Aya Tokuda, Toru Miyake, Eiji Mekata, Masaji Tani
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] Effect of hyperthermia on the cancer stem-like cells (2020)
  • Author(s): Miyuki Shimoji, Satoshi Murata, Andreas Michael Sihombing, Katsushi Takebayashi, Hirokazu Kodama, Masatsugu Kojima, Tomoyuki Ueki, Naomi Kitamura, Mina Kitamura, Aya Tokuda, Toru Miyake, Eiji Mekata, Masaji Tani.
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] Therapeutic strategy based on the mechanism of peritoneal relapse after surgery for gastric cancer (2020)
  • Author(s): Satoshi Murata, Katsushi Takebayashi, Tsuyoshi Yamaguchi, Sachiko Kaida, Ken Ishikawa, Hirokazu Kodama, Miyuki Shimoji, Andreas Michael Sihombing, Masatsugu Kojima, Toru Miyake, Hiroya Iida, Tomoyuki Ueki, Mina Kitamura, Aya Tokuda, Eiji Mekata, Masaji Tani
  • Organizer: 第79回日本癌学会学術総会