The novel cell therapy for neuroblastoma by engineered stem cell

• Project/Area Number: 15H05000
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pediatric surgery
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: Tajiri Tatsuro 京都府立医科大学, 医学(系)研究科(研究院), 教授 (80304806)
• Co-Investigator(Kenkyū-buntansha): 松田 修 京都府立医科大学, 医学(系)研究科(研究院), 教授 (00271164) ; 東 真弓 京都府立医科大学, 医学(系)研究科(研究院), 助教 (10380453) ; 文野 誠久 京都府立医科大学, 医学(系)研究科(研究院), 助教 (40405254)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥16,250,000 (Direct Cost: ¥12,500,000、Indirect Cost: ¥3,750,000); Fiscal Year 2018: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2017: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2016: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2015: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
• Keywords: 癌 / 神経芽腫 / 細胞治療 / 分化誘導 / 間葉系幹細胞 / 医療・福祉

Outline of Final Research Achievements

We analyzed the long-term tumor-homing effect of allogeneic mouse MSCs (mMSCs) and explored the anti-tumor effect and drug delivery function using IFN-Beta-mMSCs.
The IVIS revealed the accumulation of fluorescence was observed in the tumor both in vivo and after excision. Immunohistochemistry using anti-GFP antibody revealed that the mMSCs existed within the tumor until 14 days. The ELISA showed increased concentrations of IFN-β only in the tumors, with the values gradually diminishing over 14 days. The mMSCs-IFN-β group survived significantly longer than the control group, while the mMSCs-alone group did not show a survival advantage.
In conclusion, allogeneic mMSCs showed a homing ability for mouse neuroblastoma and existed within the tumor for as long as two weeks. This may be a candidate drug delivery vehicles for antitumor agents against neuroblastoma.

Academic Significance and Societal Importance of the Research Achievements

難治性神経芽腫に対する新規治療法として間葉系幹細胞（MSC）を利用したEngineered stem cell による分化誘導治療を主とした新規細胞療法について研究開発を行った．
本研究により難治性神経芽腫の治療成績向上につながる可能性がある．

Research Products

• [Journal Article] Sequential actions of immune effector cells induced by viral activation of dendritic cells to eliminate murine neuroblastoma. (2018)
  • Author(s): Kawakubo N, Tanaka S, Kinoshita Y, Tajiri T, Yonemitsu Y, Taguchi T
  • Journal Title: J Pediatr Surg Volume: 53 Pages: 1615-1620
  • DOI: 10.1016/j.jpedsurg.2017.08.019
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Results of a phase II trial for high-risk neuroblastoma treatment protocol JN-H-07: a report from the Japan Childhood Cancer Group Neuroblastoma Committee (JNBSG). (2018)
  • Author(s): Hishiki T、For the Japan Childhood Cancer Group Neuroblastoma Committee (JNBSG)、Matsumoto K、Ohira M、Kamijo T、Shichino H、Kuroda T、Yoneda A、Soejima T、Nakazawa A、Takimoto T、Yokota I、Teramukai S、Takahashi H、Fukushima T、Kaneko T、Hara J、Kaneko M、Ikeda H、Tajiri T、Nakagawara A
  • Journal Title: Int J Clin Oncol. Volume: 23 Pages: 965-973
  • DOI: 10.1007/s10147-018-1281-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Natural antibody against neuroblastoma of TH-MYCN transgenic mice does not correlate with spontaneous regression (2018)
  • Author(s): Kawakubo N, Harada Y, Ishii M, Souzaki R, Kinoshita Y, Tajiri T, Taguchi T, Yonemitsu Y
  • Journal Title: Biochem Biophys Res Commun Volume: 503 Pages: 1666-1673
  • DOI: 10.1016/j.bbrc.2018.07.097
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] In vivo effects of short- and long-term MAPK pathway inhibition against neuroblastoma (2018)
  • Author(s): Takeuchi T, Tanaka T, Higashi M, Fumino S, Iehara T, Hosoi H, Sakai T, Tajiri T
  • Journal Title: Journal of Pediatric Surgery Volume: 53 Pages: 2454-2459
  • DOI: 10.1016/j.jpedsurg.2018.08.026
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Advanced surgical strategy for giant mediastinal germ cell tumor in children (2017)
  • Author(s): Fumino S, Sakai K, Higashi M, Aoi S, Furukawa T, Yamagishi M, Inoue M, Iehara T, Hosoi H, Tajiri T
  • Journal Title: Journal of Pediatric Surgery Case Reports Volume: 27 Pages: 51-55
  • DOI: 10.1016/j.epsc.2017.09.023
  • Peer Reviewed / Open Access
• [Journal Article] Laparoscopic intraperitoneal onlay mesh for pediatric incisional hernia?a case report (2017)
  • Author(s): Inoue M, Aoi S, Taniguchi A, Sakai K, Higashi M, Fumino S, Furukawa T, Tajiri T
  • Journal Title: Surgical Case Reports Volume: 3 Pages: 122-122
  • DOI: 10.1186/s40792-017-0400-5
  • Peer Reviewed / Open Access
• [Journal Article] Efficient direct conversion of human fibroblasts into myogenic lineage induced by co-transduction with MYCL and MYOD1 (2017)
  • Author(s): Wakao J, Kishida T, Fumino S, Kimura K, Yamamoto K, Kotani SI, Mizushima K, Naito Y, Yoshikawa T, Tajiri T, Mazda O
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 488 Pages: 368-373
  • DOI: 10.1016/j.bbrc.2017.05.059
  • Peer Reviewed / Open Access
• [Journal Article] 【小児固形がんの最新トピックス】神経芽腫のトピックス． (2016)
  • Author(s): 田尻達郎
  • Journal Title: 小児外科 Volume: 48 Pages: 1185-1191
  • Peer Reviewed
• [Journal Article] 【小児固形がんの最新のトピックス】外科治療の役割と考え方． (2016)
  • Author(s): 田口智章，宗崎良太，木下義晶，田尻達郎
  • Journal Title: 小児外科 Volume: 48 Pages: 1160-1168
  • Peer Reviewed
• [Journal Article] Residual tumor in cases of intermediate-risk neuroblastoma did not influence the prognosis (2016)
  • Author(s): Iehara T, Yagyu S, Tsuchiya K, Kuwahara Y, Miyachi M, Tajiri T, Sugimoto T, Sawada T, Hosoi H
  • Journal Title: Japanese Journal of Clinical Oncology Volume: 46 Pages: 661-666
  • DOI: 10.1093/jjco/hyw050
  • Peer Reviewed
• [Journal Article] Surgical intervention and perioperative risk factors of retroperitoneal teratomas in children: a single institution experience. (2016)
  • Author(s): Fumino S, Maniwa J, Takeuchi Y, Sakai K, Higashi M, Aoi S, Furukawa T, Kimura O, Tajiri T
  • Journal Title: Pediatr Surg Int Volume: 32 Pages: 661-666
  • DOI: 10.1007/s00383-016-3938-6
  • Peer Reviewed / Open Access
• [Journal Article] MEK inhibitors as a novel therapy for neuroblastoma: Their in vitro effects and predicting their efficacy (2016)
  • Author(s): Tanaka T, Higashi M, Kimura K, Wakao J, Fumino S, Iehara T, Hosoi H, Sakai T, Tajiri T
  • Journal Title: Journal of Pediatric Surgery Volume: 51 Pages: 2074-2079
  • DOI: 10.1016/j.jpedsurg.2016.09.043
  • Peer Reviewed
• [Journal Article] 日本小児外科学会悪性腫瘍委員会:小児の外科的悪性腫瘍,2013年登録症例の全国集計結果の報告 (2015)
  • Author(s): 米倉竹夫、田尻達郎、伊勢一哉、小野 滋、大植孝治、佐藤智行、杉藤公信、菱木知郎、平井みさ子、文野誠久、本多昌平、風間理郎、杉山正彦、中田光政、荒井勇樹、脇坂宗親、近藤知史、上原秀一郎、鬼武美幸、木下義晶
  • Journal Title: 日小外会誌 Volume: 51 Pages: 96-132
  • Peer Reviewed
• [Journal Article] Validity of image-defined risk factors in localized neuroblastoma: A report from two centers in Western Japan (2015)
  • Author(s): Fumino S, Kimura K, Iehara T, Nishimura M, Nakamura S, Souzaki R, Nishie A, Taguchi T, Hosoi H, Tajiri T.
  • Journal Title: J Pediatr Surg Volume: 50 Pages: 2102-2102
  • DOI: 10.1016/j.jpedsurg.2015.08.039
  • Peer Reviewed
• [Journal Article] Validity of image-defined risk factors in localized neuroblastoma: A report from two centers in Western Japan (2015)
  • Author(s): Furukawa T, Kimura O, Sakai K, Higashi M, Fumino S, Aoi S, Tajiri T
  • Journal Title: Journal of Pediatric Surgery Volume: 50 Pages: 2025-2027
  • DOI: 10.1016/j.jpedsurg.2015.08.019
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] 巨大頸縦隔脂肪芽腫に対する頸部アプローチによる全摘術 (2015)
  • Author(s): 笹栗由貴、木村 修、樋口恒司、若尾純子、古川泰三、青井重善、文野誠久、家原知子、細井 創、田尻達郎
  • Journal Title: 小児外科 Volume: 47 Pages: 5-9
• [Journal Article] 小児の右外頸静脈に発生したvenous aneurysm の一例 (2015)
  • Author(s): 古川泰三、千葉史子、坂井宏平、樋口恒司、文野誠久、青井重善、木村 修、田尻達郎
  • Journal Title: 日小外会誌 Volume: 51 Pages: 224-227
• [Journal Article] Successful Iaparoscopic extirpation of a large omental lipoblastoma in a child. (2015)
  • Author(s): Furukawa T, Aoi S, Sakai K, Higashi M, Fumino S, Tajiri T:Successful Iaparoscopic extirpation of a large omental lipoblastoma in a child.
  • Journal Title: Asian Journal of Endoscopic Surgery Volume: 9 Pages: 473-476
• [Presentation] The Utility of Phosphorylated ERK Immunohistochemical Staining for Selecting MEK Inhibitor -Sensitive Neuroblastoma Patients (2018)
  • Author(s): Tanaka T, Takeuchi Y, Higashi M, Fumino S, Iehara T, Hosoi H, Sakai T, Tajiri T
  • Organizer: Adevances in Neuroblastoma Research 2018
  • Int'l Joint Research
• [Presentation] Preclinical trials of short- & long-term MAPK pathway inhibitors against neuroblastoma. (2018)
  • Author(s): Takeuchi Y, Tanaka T, Higashi M, Fumino S, Iehara T, Hosoi H, Sakai T, Tajiri T
  • Organizer: 51th Annual Meeting of the Pacific Association of Pediatric Surgeons
  • Int'l Joint Research
• [Presentation] 臨床応用に向けた神経芽腫 xenograft に対する MEK 阻害剤前臨床試験． (2018)
  • Author(s): 竹内雄毅，田中智子，東 真弓，文野誠久，家原知子，細井 創，酒井敏行，田尻達郎
  • Organizer: 第55回日本小児外科学会学術集会
• [Presentation] MEK阻害剤感受性神経芽腫を予測するリン酸化ERK免疫組織化学の臨床応用へ向けた検討． (2018)
  • Author(s): 竹内雄毅，田中智子，東 真弓，文野誠久，家原知子，細井 創，酒井敏行，田尻達郎
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] MEK阻害剤の至適投与時期検討を目的とした神経芽腫MRDモデルの確立． (2018)
  • Author(s): Togashi Y, Takeuchi Y, Higashi M, Fumino S, Tajiri T
  • Organizer: 第60回日本小児血液・がん学会学術集会
• [Presentation] 神経芽腫モデルマウスに対するマウス由来間葉系幹細胞を用いたdrug delivery systemの開発． (2018)
  • Author(s): Maniwa J, Kimura K, Fumino S, Tanaka T, Higashi M, Sakai K, Aoi S, Furukawa T, Kishida T, Mazda O, Tajiri T
  • Organizer: 第60回日本小児血液・がん学会学術集会
• [Presentation] Advanced Surgical Strategy for Giant Mediastinal Germ Cell Tumor in Children. (2017)
  • Author(s): Fumino S, Sakai K, Higashi M, Aoi S, Furukawa T, Yamagishi M, Inoue M, Iehara T, Hosoi H, Tajiri T
  • Organizer: 50th Annual Meeting of the Pacific Association of Pediatric Surgeons
  • Int'l Joint Research
• [Presentation] The Direct Conversion of Human Fibroblasts Toward the Myogenic Cell Lineage: The implications of Diaphragmatic Regeneration. (2017)
  • Author(s): Wakao J，Kishida T，Fumino S，Kimura K，Higashi M，Aoi S，Furukawa T，Mazda O，Tajiri T
  • Organizer: 50th Annual Meeting of the Pacific Association of Pediatric Surgeons
  • Int'l Joint Research
• [Presentation] Immunohistochemical analysis of pre- and post-chemotherapeutic ERK phosphorylation in clinical neuroblastoma samples. (2017)
  • Author(s): Tanaka T,Takeuchi Y，Higashi M，Fumino S，Iehara T，Hosoi H，Sakai T，Tajiri T
  • Organizer: 3rd Asia-Pacific International Symposium of Neuroblastoma
  • Int'l Joint Research
• [Presentation] Preclinical study of novel MEK inhibitors on neuroblastoma and the biomarker for their therapeutic effects in neuroblastoma xenograft mice. (2017)
  • Author(s): Takeuchi Y, Tanaka T, Higashi M, Fumino S, Iehara T, Hosoi H, Sakai T, Tajiri T.
  • Organizer: 3rd Asia-Pacific International Symposium of Neuroblastoma
  • Int'l Joint Research
• [Presentation] Current surgical intervention for pediatric giant mediastinal germ cell tumors. (2017)
  • Author(s): Fumino S, Sakai K, Higashi M, Aoi S, Furukawa T, Yamagishi M, Inoue M, Iehara T, Hosoi H, Tajiri T
  • Organizer: 49th Congress of the International Society of Paediatric Oncology (SIOP)
  • Int'l Joint Research
• [Presentation] Treatment strategies for different types of lymphangioma. 28-years experience in a single institution. (2016)
  • Author(s): 17)Kimura O, Furukawa T, Fumino S, Aoi S, Tajiri T
  • Organizer: 68th Annual Autum Congress of the Korean Surgical Society,
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2016-11-03
  • Int'l Joint Research
• [Presentation] Retroperitoneal teratomas in children: still challenging for surgeons. (2016)
  • Author(s): Fumino S, Maniwa J, Takeuchi Y, Sakai K, Higashi M, Aoi S, Furukawa T, Kimura O, Tajiri T
  • Organizer: 40th World Congress of the International College of Surgeons
  • Place of Presentation: 京都
  • Year and Date: 2016-10-24
  • Int'l Joint Research
• [Presentation] JNK-STAT3 pathway in neuroblastoma. (2016)
  • Author(s): Higashi M, Sakai K, Fumino S, Aoi S, Furukawa T, Tajiri T
  • Organizer: 40th World Congress of the International College of Surgeons
  • Place of Presentation: 京都
  • Year and Date: 2016-10-24
  • Int'l Joint Research
• [Presentation] Immunohistochemical staining of phosphorylated-ERK as a predictor of therapeutic effects of MEK inhibitors on neuroblastoma. (2016)
  • Author(s): Tanaka T, Higashi M, Wakao J, Kimura K Fumino S, Iehara T, Hosoi H, Sakai T, Tajiri T
  • Organizer: 40th World Congress of the International College of Surgeons,
  • Place of Presentation: 京都
  • Year and Date: 2016-10-24
  • Int'l Joint Research
• [Presentation] Perioperative management and surgical intervention for retroperitoneal teratomas in children. (2016)
  • Author(s): Fumino S, Maniwa J, Takeuchi Y, Sakai K, Higashi M, Aoi S, Furukawa T, Kimura O, Tajiri T
  • Organizer: 48th Congress of the International Society of Paediatric Oncology (SIOP)
  • Place of Presentation: Dublin, Ireland.
  • Year and Date: 2016-10-19
  • Int'l Joint Research
• [Presentation] Delayed local treatment for high risk neuroblastoma - from the Japan neuroblastoma study group trial [Multidisciplinary team “IPSO-PROS-SIOP” symposium]. (2016)
  • Author(s): Yoneda A, Tajiri T, Hishiki T
  • Organizer: 48th Congress of the International Society of Paediatric Oncology (SIOP)
  • Place of Presentation: Dublin, Ireland.
  • Year and Date: 2016-10-19
  • Int'l Joint Research
• [Presentation] A phase II study of bold delayed local control strategy in children with high risk neuroblastoma: Japan neuroblastoma study group (JN-H-11) trial. (2016)
  • Author(s): Shichino H, Mugishima H, Matsumoto K, Hishiki T, Iehara T, Yoneda A, Soejima T, Takimoto T, Takahashi H, Teramukai S, Kamijo T, Nakazawa A, Fukushima T, Hosoi H, Tajiri T, Nakagawara A
  • Organizer: 48th Congress of the International Society of Paediatric Oncology (SIOP)
  • Place of Presentation: Dublin, Ireland.
  • Year and Date: 2016-10-19
  • Int'l Joint Research
• [Presentation] Postoperative bowel management for the patients with anorectal malformation associating spinal lesions: A single institute experience. (2016)
  • Author(s): Aoi S, Furukawa T, Higashi M, Sakai K, Fumino S, Kimura O, Tajiri T
  • Organizer: International Children's Continence Society
  • Place of Presentation: 京都
  • Year and Date: 2016-06-30
  • Int'l Joint Research
• [Presentation] Primary tumor resection after high dose chemotherapy with autologous hematopoietic stem cell transplantation is a safe and feasible option. A report from the Japanese Neuroblastoma Study Group (JNBSG). (2016)
  • Author(s): Hishiki T, Yoneda A, Kuroda T, Tokiwa K, Ise K, Ono S, Kinoshita Y, Uehara S, Matsumoto K, Kumagai M, Shichino H, Soejima T, Takimoto T, Hara J, Tajiri T, Nakagawara A
  • Organizer: Advances in Neuroblastoma Research (ANR)
  • Place of Presentation: Queensland, Australia.
  • Year and Date: 2016-06-19
  • Int'l Joint Research
• [Presentation] Genomic characterization of high-risk neuroblastoma in Japan: A retrospective study of 537 cases by using updated follow-up data based on INRG variables [Japan Neuroblastoma Study Group (JNBSG)]. (2016)
  • Author(s): Ohira M, Kamijo T, Takimoto T, Nakazawa A, Matsumoto K, Shichino H, Hishiki T, Iehara T, Nakamura Y, Nagase H, Yoneda A, Fukushima T, Tajiri T, Nakagawara A
  • Organizer: Advances in Neuroblastoma Research (ANR)
  • Place of Presentation: Queensland, Australia.
  • Year and Date: 2016-06-19
  • Int'l Joint Research
• [Presentation] Opsoclonus-myoclonus syndrome in neuroblastoma: A report from the Japan Neuroblastoma Study Group (JNBSG). (2016)
  • Author(s): Iehara T, Yoneda A, Takama Y, Arakawa Y, Koh K, Yagyu S, Hosoi H, Tajiri T, Nakagawara A
  • Organizer: Advances in Neuroblastoma Research (ANR)
  • Place of Presentation: Queensland, Australia.
  • Year and Date: 2016-06-19
  • Int'l Joint Research
• [Presentation] MEK inhibitors as a novel therapy for neuroblastoma: Their in vitro effects & predicting their efficacy. (2016)
  • Author(s): Tanaka T, Higashi M, Kimura K, Wakao J, Fumino S, Iehara T, Hosoi H, Sakai T, Tajiri T
  • Organizer: 49th Annual Meeting of the Pacific Association of Pediatric Surgeons (PAPS)
  • Place of Presentation: Kauai, USA
  • Year and Date: 2016-05-17
  • Int'l Joint Research
• [Presentation] Surgical management and perioperative risk factors of retroperitoneal teratomas in children: A single institution experience. (2016)
  • Author(s): Fumino S, Maniwa J, Takeuchi Y, Sakai K, Higashi M, Aoi S, Furukawa T, Kimura O, Tajiri T
  • Organizer: 49th Annual Meeting of the Pacific Association of Pediatric Surgeons (PAPS)
  • Place of Presentation: Kauai, USA
  • Year and Date: 2016-05-17
  • Int'l Joint Research
• [Presentation] A clinical trial of low-dose mTOR inhibitor therapy for the treatment of children with refractory lymphatic anomaly. (2016)
  • Author(s): Furukawa T, Sakai K, Higashi M, Fumino S, Aoi S, Kimura O, Ozeki M, Tajiri T
  • Organizer: 49th Annual Meeting of the Pacific Association of Pediatric Surgeons (PAPS)
  • Place of Presentation: Kauai, USA
  • Year and Date: 2016-05-17
  • Int'l Joint Research
• [Presentation] Tumor-homing effect of human mesenchymal stem cells in a TH-MYCN mouse model of neuroblastoma. (2016)
  • Author(s): Kimura K, Kishida T, Wakao J, Tanaka T, Higashi M, Fumino S, Aoi S, Furukawa T, Mazda O, Tajiri T
  • Organizer: 49th Annual Meeting of the Pacific Association of Pediatric Surgeons (PAPS)
  • Place of Presentation: Kauai, USA
  • Year and Date: 2016-05-17
  • Int'l Joint Research
• [Presentation] Thoracoscopic resection of ectopic mediastinal parathyroid adenoma utilizing gamma probe and intraoperative PTH monitoring in a child. (2016)
  • Author(s): Furukawa T, Fumino S, Sakai K, Higashi M, Aoi S, Tajiri T
  • Organizer: IPEG’s 25th Annual Congress for Endosurgery in Children
  • Place of Presentation: 福岡
  • Int'l Joint Research
• [Book] 標準小児外科学 第7版 第22章小児腫瘍 B神経芽腫 (2017)
  • Author(s): 髙松 英夫 田尻達郎
  • Total Pages: 432
  • Publisher: 医学書院
  • ISBN: 9784260027809
• [Book] スタンダード小児がん手術 : 臓器別アプローチと手技のポイント (2017)
  • Author(s): 田口 智章、黒田 達夫
  • Total Pages: 313
  • Publisher: メジカルビュー社
  • ISBN: 9784758304658
• [Book] Ⅷ．血液，腫瘍 固形腫瘍（神経芽腫） (2017)
  • Author(s): 山岸 敬幸 田尻達郎
  • Total Pages: 407
  • Publisher: 診断と治療社
• [Book] Operative general surgery in neonates and infant.PartⅦ Tumors 60 Neuroblastoma. (2016)
  • Author(s): Tajiri T
  • Total Pages: 402
  • Publisher: Springer
• [Book] 小児疾患診療のための病態生理 改訂第5版【Ⅶ．血液・腫瘍性疾患】性腺腫瘍 (2016)
  • Author(s): 文野誠久，田尻達郎
  • Total Pages: 5
  • Publisher: 東京医学社
• [Book] チャイルドヘルス Vol 日本における小児悪性固形腫瘍の治療とグループスタディの現状 (2015)
  • Author(s): 田尻達郎
  • Total Pages: 80
  • Publisher: 診断と治療社