Development of a novel therapeutic approach for pediatric malignant solid tumors using NKT cell-mediated immune system

• Project/Area Number: 23592624
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatric surgery
• Research Institution: Chiba Cancer Center (Research Institute) (2013); Chiba University (2011-2012)
• Principal Investigator: HISHIKI TOMORO 千葉県がんセンター(研究所), 発がん研究グループ, 主任医長 (00375776)
• Co-Investigator(Kenkyū-buntansha): YOSHIDA Hideo 千葉大学, 大学院医学研究院, 教授 (60210712) ; MOTOHASHI Shinichiro 千葉大学, 大学院医学研究院, 教授 (60345022) ; KAMIJO Takehiko 千葉県がんセンター, 発がん研究部, 部長 (90262708)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2012: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2011: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 神経芽腫 / 免疫療法 / NKT細胞 / 小児悪性固形腫瘍

Research Abstract

The prognosis of patients with pediatric malignant solid tumors have dramatically improved, although a part of these tumors are yet aggressive and fatal. Survivors suffer from grave side effects as a result of multimodal therapy, and the QOL of these patients are not satisfactory. In the present preclinical study, we aimed to develop a novel therapeutic approach for these tumors. NKT cells were detected in tumor-burden patients and were expandable in vitro. These cells showed significant cytotoxicity against neuroblastoma cell lines. Clinical implication of NKT mediated immunotherapy is awaited on the basis of these results.

Research Products

• [Journal Article] Novel 1p tumour suppressor Dnmt1- associated protein 1 regulates MYCN/ ataxia telangiectasia mutated/p53 pathway (2014)
  • Author(s): Yamaguchi Y, Takenobu H, Ohira M, Nakazawa A, Yoshida S, Akita N, Shimozato O, Iwama A, Nakagawara A, Kamijo T
  • Journal Title: Eur J Cancer Volume: 50 Pages: 1555-1565
• [Journal Article] Novel 1p tumour suppressor Dnmt1-associated protein 1 regulates MYCN/ataxia telangiectasia mutated/p53 pathway. (2014)
  • Author(s): Yamaguchi Y, Takenobu H, Ohira M, Nakazawa A, Yoshida S, Akita N, Shimozato O, Iwama A, Nakagawara A, Kamijo T.
  • Journal Title: Eur J Cancer Volume: 50 Pages: 1555-1565
  • DOI: 10.1016/j.ejca.2014.01.023
  • Peer Reviewed
• [Journal Article] Current therapeutic strategies for childhood hepatic tumors : surgical and interventional treatments for hepatoblastoma (2013)
  • Author(s): Hishiki T
  • Journal Title: Int J Clin Oncol Volume: 18 Pages: 962-968
• [Journal Article] Optimal surgical treatment and urological outcomes in boys with pelvic and urogenital rhabdomyosarcomas and soft tissue sarcomas (2013)
  • Author(s): Hishiki T, Saito T, Mitsunaga T, Nakata M, Terui E, Komatsu S, Mise N, Harada K, Iwai J, Higashimoto Y, Okimoto Y, Kakuda H, Ochiai H, Hino M, Homma S, Osa Y, Yoshida H
  • Journal Title: Pediatr Surg Int Volume: 29 Pages: 1077-1082
• [Journal Article] NKT Cells as an Ideal Anti- Tumor Immunotherapeutic (2013)
  • Author(s): Fujii SI, Shimizu K, Okamoto Y, Kunii N, Nakayama T, Motohashi S, Taniguchi M
  • Journal Title: Front Immunol Volume: 2 Pages: 409
• [Journal Article] Current therapeutic strategies for childhood hepatic tumors: surgical and interventional treatments for hepatoblastoma. (2013)
  • Author(s): Hishiki T.
  • Journal Title: Int J Clin Oncol Volume: 18 Pages: 962-968
  • DOI: 10.1007/s10147-013-0625-7
• [Journal Article] A cisplatin plus pirarubicin-based JPLT2 chemotherapy for hepatoblastoma: experience and future of the Japanese Study Group for Pediatric Liver Tumor (JPLT). (2013)
  • Author(s): Hiyama E, Ueda Y, Onitake Y, Kurihara S, Watanabe K, Hishiki T, Tajiri T, Ida K, Yano M, Kondo S, Oue T; Japanese Study Group for Pediatric Liver Tumor.
  • Journal Title: Pediatr Surg Int. Volume: 29 Pages: 1071-1075
  • DOI: 10.1007/s00383-013-3399-0..
  • Peer Reviewed
• [Journal Article] Optimal surgical treatment and urological outcomes in boys with pelvic and urogenital rhabdomyosarcomas and soft tissue sarcomas. (2013)
  • Author(s): Hishiki T, Saito T, Mitsunaga T, Nakata M, Terui E, Komatsu S, Mise N, Harada K, Iwai J, Higashimoto Y, Okimoto Y, Kakuda H, Ochiai H, Hino M, Homma S, Osa Y, Yoshida H.
  • Journal Title: Pediatr Surg Int Volume: 29 Pages: 1077-1082
  • DOI: 10.1007/s00383-013-3400-y
• [Journal Article] NKT Cells as an Ideal Anti-Tumor Immunotherapeutic. (2013)
  • Author(s): Fujii SI, Shimizu K, Okamoto Y, Kunii N, Nakayama T, Motohashi S, Taniguchi M
  • Journal Title: Front Immunol Volume: 2 Pages: 409
• [Journal Article] Novel adaptor protein Shf interacts with ALK receptor and negatively regulates its downstream signals in neuroblastoma. (2013)
  • Author(s): Takagi D, Tatsumi Y, Yokochi T, Takatori A, Ohira M, Kamijo T, Kondo S, Fujii Y, Nakagawara A.
  • Journal Title: Cancer Sci Volume: 104 Pages: 563-572
  • DOI: 10.1111/cas.12115.
  • Peer Reviewed
• [Journal Article] Surgical strategies for unresectable hepato- blastomas (2012)
  • Author(s): Tajiri T, Kimura O, Fumino S, Furukawa T, Iehara T, Souzaki R, Kinoshita Y, Koga Y, Suminoe A, Hara T, Kohashi K, Oda Y, Hishiki T, Hosoi H, Hiyama E, Taguchi T
  • Journal Title: J Pediatr Surg Volume: 47 Pages: 2194-2198
• [Journal Article] Regulation of memory CD4 T-cell pool size and function by natural killer T cells in vivo (2012)
  • Author(s): Iwamura C, Shinoda K, Endo Y, Watanabe Y, Tumes DJ, Motohashi S, Kawahara K, Kinjo Y, Nakayama T
  • Journal Title: Proc Natl Acad Sci U S A Volume: 109 Pages: 16992-16997
• [Journal Article] Accumulation of activated invariant natural killer T cells in the tumor microenvironment afterα- galactosylceramide - pulsed antigen presenting cells (2012)
  • Author(s): Nagato K, Motohashi S, Ishibashi F, Okita K, Yamasaki K, Moriya Y, Hoshino H, Yoshida S, Hanaoka H, Fujii S, Taniguchi M, Yoshino I, Nakayama T
  • Journal Title: J Clin Immunol Volume: 32 Pages: 1071-1081
• [Journal Article] Surgical strategies for unresectable hepatoblastomas. (2012)
  • Author(s): Tajiri T, Kimura O, Fumino S, Furukawa T, Iehara T, Souzaki R, Kinoshita Y, Koga Y, Suminoe A, Hara T, Kohashi K, Oda Y, Hishiki T, Hosoi H, Hiyama E, Taguchi T.
  • Journal Title: J Pediatr Surg. Volume: 47 Pages: 2194-2198
  • DOI: 10.1016/j.jpedsurg.2012.09.006.
  • Peer Reviewed
• [Journal Article] Regulation of memory CD4 T-cell pool size and function by natural killer T cells in vivo. (2012)
  • Author(s): Iwamura C, Shinoda K, Endo Y, Watanabe Y, Tumes DJ, Motohashi S, Kawahara K, Kinjo Y, Nakayama T.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 109 Pages: 16992-16997
  • DOI: 10.1073/pnas.1203494109.
  • Peer Reviewed
• [Journal Article] The transcription factor Sox4 is a downstream target of signaling by the cytokine TGF-β and suppresses T(H)2 differentiation. (2012)
  • Author(s): Kuwahara M, Yamashita M, Shinoda K, Tofukuji S, Onodera A, Shinnakasu R, Motohashi S, Hosokawa H, Tumes D, Iwamura C, Lefebvre V, Nakayama T.
  • Journal Title: Nat Immunol Volume: 13 Pages: 778-786
  • DOI: 10.1038/ni.2362
  • Peer Reviewed
• [Journal Article] Accumulation of activated invariant natural killer T cells in the tumor microenvironment after α-galactosylceramide-pulsed antigen presenting cells. (2012)
  • Author(s): Nagato K, Motohashi S, Ishibashi F, Okita K, Yamasaki K, Moriya Y, Hoshino H, Yoshida S, Hanaoka H, Fujii S, Taniguchi M, Yoshino I, Nakayama T.
  • Journal Title: J Clin Immunol Volume: 32 Pages: 1071-181
  • DOI: 10.1007/s10875-012-9697-9
  • Peer Reviewed
• [Journal Article] Murine Schnurri-2 controls natural killer cell function and lymphoma development. (2012)
  • Author(s): Yamashita J, Iwamura C, Mitsumori K, Hosokawa H, Sasaki T, Takahashi M, Tanaka H, Kaneko K, Hanazawa A, Watanabe Y, Shinoda K, Tumes D, Motohashi S, Nakayama T.
  • Journal Title: Leuk Lymphoma Volume: 53 Pages: 479-486
  • DOI: 10.3109/10428194.2011.625099
  • Peer Reviewed
• [Journal Article] NLRR1 enhances EGF-mediated MYCN induction in neuroblastoma and accelerates tumor growth in vivo. (2012)
  • Author(s): Hossain S, Takatori A, Nakamura Y, Suenaga Y, Kamijo T, Nakagawara A.
  • Journal Title: Cancer Res Volume: 72 Pages: 4587-4596
  • DOI: 10.1158/0008-5472.CAN-12-0943
  • Peer Reviewed
• [Journal Article] Anti-tumor immune responses induced by iNKT cell-based immunotherapy for lung cancer and head and neck cancer (2011)
  • Author(s): Motohashi S, et al
  • Journal Title: Clin Immunol Volume: 140 Pages: 167-176
• [Journal Article] Induction of NKT cell-specific immune responses in cancer tissues after NKT cell-targeted adoptive immunotherapy (2011)
  • Author(s): Yamasaki K, Motohashi S, et al
  • Journal Title: Clin Immunol Volume: 138 Pages: 256-265
• [Journal Article] Migration and immunological reaction after the administration ofαGalCer-pulsed antigen-presenting cells into the submucosa of patients with head and neck cancer (2011)
  • Author(s): Kurosaki M, Motohashi S, et al
  • Journal Title: Cancer Immunol Immunother Volume: 60 Pages: 207-215
• [Journal Article] Anti-tumor immune responses induced by iNKT cell-based immunotherapy for lung cancer and head and neck cancer. (2011)
  • Author(s): Motohashi et al
  • Journal Title: Clin Immunol. Volume: 140 Pages: 167-176
  • Peer Reviewed
• [Journal Article] Induction of NKT cell-specific immune responses in cancer tissues after NKT cell-targeted adoptive immunotherapy. (2011)
  • Author(s): Yamasaki K, Motohashi S, et al
  • Journal Title: Clin Immunol. Volume: 138 Pages: 255-265
  • Peer Reviewed
• [Presentation] 神経芽腫細胞に対するNKT細胞によるADCC増強効果の検討 (2013)
  • Author(s): 三瀬 直子, 菱木 知郎, 斎藤 武, 照井 慶太, 光永 哲也, 中田 光政, 國井 直樹, 藤川 陽, 堀中 敦史, 鎌田 稔子, 蒔田 勇治, 内田 亮介, 伊原 史英, 吉田 英生, 本橋 新一郎
  • Organizer: 第55回 日本小児血液・がん学会学術集会
  • Place of Presentation: 福岡
  • Year and Date: 20131129-20131201
• [Presentation] 小児悪性固形腫瘍に対するNKT細胞系を用いた新規免疫療法の開発研究 (2013)
  • Author(s): 菱木知郎
  • Organizer: 第50回 日本小児外科学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 20130529-20130531
• [Presentation] 小児悪性固形腫瘍に対するNKT細胞系を用いた新規免疫療法の開発研究 (2013)
  • Author(s): 菱木知郎
  • Organizer: 第50回日本小児外科学会学術集会
  • Year and Date: 2013-05-29
• [Presentation] Review of surgical treatment in patients enrolled in the JNBSG high risk neuroblastoma clinical trial (A phase II study of multidisciplinary approach to establish standard treatment for advanced neuroblastoma) (2012)
  • Author(s): 菱木知郎
  • Organizer: A report from Japan Neuroblatoma Study Group (JNBSG).第54回日本小児血液・がん学会学術集会
  • Year and Date: 2012-12-10
• [Presentation] 小児悪性固形腫瘍に対するNKT細胞系を用いた新規免疫療法の開発研究 (2012)
  • Author(s): 菱木知郎
  • Organizer: 第54回日本小児血液・がん学会学術集会
  • Year and Date: 2012-12-10
• [Presentation] 神経芽腫細胞に対するNKT細胞によるADCC増強効果の検討
  • Author(s): 三瀬直子, 菱木知郎, 斎藤武, 照井慶太, 光永哲也, 中田光政, 國井直樹, 藤川陽, 堀中敦史, 鎌田稔子, 蒔田勇治, 内田亮介, 伊原史英, 吉田英生, 本橋新一郎
  • Organizer: 第55回日本小児血液・がん学会学術集会
• [Presentation] Review of surgical treatment in patients enrolled in the JNBSG high risk neuroblastoma clinical trial (A phase II study of multidisciplinary approach to establish standard treatment for advanced neuroblastoma) ̶ A report from Japan Neuroblatoma Study Group (JNBSG)
  • Author(s): 菱木 知郎
  • Organizer: 第５４回 日本小児血液・がん学会学術集会
  • Place of Presentation: 横浜
• [Presentation] 小児悪性固形腫瘍に対する NKT 細胞系を用いた新規免疫療法の開発研究
  • Author(s): 菱木 知郎
  • Organizer: 第５４回 日本小児血液・がん学会学術集会
  • Place of Presentation: 横浜