悪性黒色腫に対するiPS細胞由来ミエロイドラインによる新規免疫療法の開発

2016 Fiscal Year Research-status Report

• Project/Area Number: 15K09772
• Research Institution: Kumamoto University
• Principal Investigator: 福島 聡 熊本大学, 医学部附属病院, 講師 (50398210)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: 悪性黒色腫 / 免疫療法 / マクロファージ / iPS細胞 / 免疫細胞療法 / インターフェロン / IL-15

Outline of Annual Research Achievements

ヒトメラノーマ株の免疫不全マウスでの腹膜播種をヒトiPS細胞由来マクロファージ（iPS-MP）の有効性に関しては、前年度までに得られた成果を発表した。(Cancer Immunol Res. 2016 4:248-58. )
今年度は、免疫系を有するB6マウスにおいて、同系のiPS-MPを投与したマウスでの検討を進めていった。まず、ヒトiPS-MPにおける知見から、インターフェロンβを遺伝子導入したiPS-MPでの治療実験を行ったが、マウスでも有意にコントロールに対して有意に強力な抗腫瘍効果を示した。さらに効果を増強するために、抗腫瘍サイトカインであるIL-15の遺伝子導入を行った。このとき、単にIL-15を遺伝子導入した細胞ではIL-15は細胞外に分泌されなかったが、IL-15Rαを共導入することで、高いIL-15分泌能を持つiPS-MPを得た。これらの細胞を用いて、in vivoイメージングで抗腫瘍効果を観察したところ、インターフェロンβ、IL-15単独に比べて、両方を混じて治療した群においてより強い抗腫瘍効果を確認した。
またiPS細胞による細胞治療を臨床応用にもっていくためには、腫瘍化のリスクを検証することが極めて重要である。そこでMHC完全一致マウス由来のiPS-MPと、一つだけMHCが一致しないsemiallogenicなマウスES細胞由来マクロファージを用いて実験を行ったところ、同等の効果を確認した。さらに、MHC完全一致マウス由来iPS-MPが長期観察すると同系マウス体内で腫瘍化すること、逆に、semiallogenicな治療細胞は腫瘍化しないことを確認した。またこのとき、自己免疫現象も発生しないことを確かめた。

Current Status of Research Progress

1: Research has progressed more than it was originally planned.

Reason

上述の成果については、すでに論文投稿準備中である。当初計画からすると、早い進行である。理由としては、当初予想した結果が、実験により順調に得られていることが挙げられる。

Strategy for Future Research Activity

上述の効果を裏付けする、抗腫瘍効果のメカニズムについてさらなる検討を加えていく。また、順当に論文発表に至った場合は、今後は、さらに別の免疫活性化分子の遺伝子導入を検討し、より強い抗腫瘍効果の発現を目指して研究を推進していく。

Causes of Carryover

計画当初より、３年間で実行する研究計画である。

Expenditure Plan for Carryover Budget

次年度は、本年度までに得られた抗腫瘍効果のメカニズムの解析、さらに抗腫瘍効果を高めるための新規遺伝子導入実験などに予算を使用する予定である。

Research Products

• [Int'l Joint Research] The University of Chicago/University of California(米国)
  • Country Name: U.S.A.
  • Counterpart Institution: The University of Chicago/University of California
• [Int'l Joint Research] Hospital of Zurich(スイス)
  • Country Name: SWITZERLAND
  • Counterpart Institution: Hospital of Zurich
• [Journal Article] Transforming growth factor β inhibitor Repsox down-regulates collagen expression of scleroderma dermal fibroblasts and prevents bleomycin-induced mice skin fibrosis. (2017)
  • Author(s): Ide M, Jinnin M, Tomizawa Y, Wang Z, Kajihara I, Fukushima S, Hashizume Y, Asano Y, Ihn H.
  • Journal Title: Exp Dermatol Volume: 印刷中 Pages: 印刷中
  • DOI: 10.1111/exd.13366.
  • Peer Reviewed
• [Journal Article] Serum levels of genomic DNA of α1(I) collagen are elevated in scleroderma patients. (2017)
  • Author(s): Sawamura S, Jinnin M, Shimbara M, Nakamura K, Kudo H, Inoue K, Nakayama W, Kajihara I, Fukushima S, Ihn H.
  • Journal Title: J Dermatol. Volume: 印刷中 Pages: 印刷中
  • DOI: 10.1111/1346-8138.13838.
  • Peer Reviewed
• [Journal Article] Inhibition of HSP90 exerts anti-tumor effect on angiosarcoma: Involvement of VEGF signaling pathway. (2017)
  • Author(s): Yamada-Kanazawa S, Kajihara I, Fukushima S, Jinnin M, Masuzawa M, Masuzawa M, Amoh Y, Hoshina D, Abe R, Ihn H.
  • Journal Title: Br J Dermatol. Volume: 印刷中 Pages: 印刷中
  • DOI: 10.1111/bjd.15303.
• [Journal Article] The expression of miR-124 increases in aged skin to cause cell senescence and it decreases in squamous cell carcinoma. (2017)
  • Author(s): Harada M, Jinnin M, Wang Z, Hirano A, Tomizawa Y, Kira T, Igata T, Masuguchi S, Fukushima S, Ihn H.
  • Journal Title: Biosci Trends. Volume: 6 Pages: 454-459
  • DOI: 10.5582/bst.2016.01102.
  • Peer Reviewed
• [Journal Article] Diagnosis of nail psoriasis: evaluation of nail-derived microRNAs as potential novel biomarkers. (2017)
  • Author(s): Wang Z, Jinnin M, Harada M, Kudo H, Inoue K, Nakayama W, Honda N, Makino K, Kajihara I, Fukushima S, Ihn H.
  • Journal Title: Eur J Dermatol. Volume: 1 Pages: 20-27
  • DOI: 10.1684/ejd.2016.2906.
  • Peer Reviewed
• [Journal Article] Dysregulated interleukin-23 signalling contributes to the increased collagen production in scleroderma fibroblasts via balancing microRNA expression. (2017)
  • Author(s): Nakayama W, Jinnin M, Tomizawa Y, Nakamura K, Kudo H, Inoue K, Makino K, Honda N, Kajihara I, Fukushima S, Ihn H.
  • Journal Title: Rheumatology (Oxford). Volume: 1 Pages: 145-155
  • DOI: 10.1093/rheumatology/kew336.
  • Peer Reviewed
• [Journal Article] Systemic lupus erythematosus associated with myasthenia gravis, pemphigus foliaceus and chronic thyroiditis after thymectomy. (2017)
  • Author(s): Sawamura S, Kajihara I, Makino K, Makino T, Fukushima S, Jinnin M, Oyama B, Hashimoto T, Ihn H.
  • Journal Title: Australas J Dermatol. Volume: 印刷中 Pages: 印刷中
  • DOI: 10.1111/ajd.12510.
  • Peer Reviewed
• [Journal Article] AT-rich Interaction Domain-containing Protein 3B is a New Tumour Marker for Melanoma. (2017)
  • Author(s): Nakahara S, Fukushima S, Yamashita J, Kubo Y, Tokuzumi A, Miyashita A, Harada M, Nakamura K, Jinnin M, Ihn H.
  • Journal Title: Acta Derm Venereol. Volume: 1 Pages: 112-114
  • DOI: 10.2340/00015555-2449.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Exome sequence analysis of Kaposiform hemangioendothelioma: identification of putative driver mutations. (2016)
  • Author(s): Egashira S, Jinnin M, Harada M, Masuguchi S, Fukushima S, Ihn H.
  • Journal Title: An Bras Dermatol. Volume: 6 Pages: 748-753
  • DOI: 0.1590/abd1806-4841.20165026.
  • Peer Reviewed
• [Journal Article] Peripheral blood Th9 cells are a possible pharmacodynamic biomarker of nivolumab treatment efficacy in metastatic melanoma patients. (2016)
  • Author(s): Nonomura Y, Otsuka A, Nakashima C, Seidel JA, Kitoh A, Dainichi T, Nakajima S, Sawada Y, Matsushita S, Aoki M, Takenouchi T, Fujimura T, Hatta N, Koreeda S, Fukushima S, Honda T, Kabashima K.
  • Journal Title: Oncoimmunology. Volume: 12 Pages: -
  • DOI: 10.1080/2162402X.2016.1248327.
  • Peer Reviewed
• [Journal Article] Intratumoral expression levels of PD-L1, GZMA, and HLA-A along with oligoclonal T cell expansion associate with response to nivolumab in metastatic melanoma. (2016)
  • Author(s): Inoue H, Park JH, Kiyotani K, Zewde M, Miyashita A, Jinnin M, Kiniwa Y, Okuyama R, Tanaka R, Fujisawa Y, Kato H, Morita A, Asai J, Katoh N, Yokota K, Akiyama M, Ihn H, Fukushima S, Nakamura Y.
  • Journal Title: Oncoimmunology. Volume: - Pages: -
  • DOI: 10.1080/2162402X.2016.1204507
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Upregulation of ANGPTL6 in mouse keratinocytes enhances susceptibility to psoriasis. (2016)
  • Author(s): Tanigawa H, Miyata K, Tian Z, Aoi J, Kadomatsu T, Fukushima S, Ogata A, Takeda N, Zhao J, Zhu S, Terada K, Endo M, Morinaga J, Sugizaki T, Sato M, Morioka MS, Manabe I, Mashimo Y, Hata A, Taketomi Y, Yamamoto K, Murakami M, Araki K, Jinnin M, Ihn H, Oike Y.
  • Journal Title: Sci Rep. Volume: - Pages: -
  • DOI: 10.1038/srep34690.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Establishment and gene expression analysis of disease-derived induced pluripotent stem cells of scleroderma. (2016)
  • Author(s): Wang Z, Nakamura K, Jinnin M, Kudo H, Goto M, Era T, Kira T, Nakashima T, Fukushima S, Ihn H.
  • Journal Title: J Dermatol Sci. Volume: 2 Pages: 186-196
  • DOI: 10.1016/j.jdermsci.2016.08.002.
  • Peer Reviewed
• [Journal Article] Altered expression of CD63 and exosomes in scleroderma dermal fibroblasts. (2016)
  • Author(s): Nakamura K, Jinnin M, Harada M, Kudo H, Nakayama W, Inoue K, Ogata A, Kajihara I, Fukushima S, Ihn H.
  • Journal Title: J Dermatol Sci. Volume: 1 Pages: 30-39
  • DOI: 10.1016/j.jdermsci.2016.06.013.
  • Peer Reviewed
• [Journal Article] Myasthenic crisis and polymyositis induced by one dose of nivolumab. (2016)
  • Author(s): Kimura T, Fukushima S, Miyashita A, Aoi J, Jinnin M, Kosaka T, Ando Y, Matsukawa M, Inoue H, Kiyotani K, Park JH, Nakamura Y, Ihn H.
  • Journal Title: Cancer Sci. Volume: 7 Pages: 1055-1058
  • DOI: 10.1111/cas.12961.
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Cell division cycle-associated protein 1 as a new melanoma-associated antigen. (2016)
  • Author(s): Tokuzumi A, Fukushima S, Miyashita A, Nakahara S, Kubo Y, Yamashita J, Harada M, Nakamura K, Kajihara I, Jinnin M, Ihn H.
  • Journal Title: J Dermatol. Volume: 12 Pages: 1399-1405
  • DOI: 10.1111/1346-8138.13436.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Cytokine expression profiles in the sera of cutaneous squamous cell carcinoma patients. (2016)
  • Author(s): Yamada S, Jinnin M, Kajihara I, Nakashima T, Aoi J, Harada M, Igata T, Masuguchi S, Fukushima S, Ihn H.
  • Journal Title: Drug Discov Ther. Volume: 3 Pages: 172-176
  • DOI: 10.5582/ddt.2016.01032.
  • Peer Reviewed
• [Journal Article] Symptomless Pulmonary Cryptococcosis in a Psoriatic Arthritis Patient during Infliximab Therapy. (2016)
  • Author(s): Yamada S, Kajihara I, Johno T, Fukushima S, Jinnin M, Masunaga A, Kohrogi H, Ihn H.
  • Journal Title: Ann Dermatol. Volume: 2 Pages: 269-270
  • DOI: 10.5021/ad.2016.28.2.269.
  • Peer Reviewed / Open Access
• [Journal Article] Frequency of level II and III axillary nodes metastases in patients with positive sentinel lymph nodes in melanoma: a multi-institutional study in Japan. (2016)
  • Author(s): Tsutsumida A, Takahashi A, Namikawa K, Yamazaki N, Uhara H, Teramoto Y, Takenouchi T, Fukushima S, Yokota K, Uehara J, Matsushita S, Shibayama Y, Hatta N, Masui Y, Uchi H, Fujisawa Y, Ogata D.
  • Journal Title: Int J Clin Oncol. Volume: 4 Pages: 796-800
  • DOI: 10.1007/s10147-015-0944-y.
  • Peer Reviewed
• [Journal Article] Immunotherapy against Metastatic Melanoma with Human iPS Cell-Derived Myeloid Cell Lines Producing Type I Interferons. (2016)
  • Author(s): Miyashita A, Fukushima S, Nakahara S, Kubo Y, Tokuzumi A, Yamashita J, Aoi J, Haruta M, Senju S, Nishimura Y, Jinnin M, Ihn H.
  • Journal Title: Cancer Immunol Res. Volume: 3 Pages: 248-258
  • DOI: 10.1158/2326-6066.CIR-15-0096.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The role of PSMB9 upregulated by interferon signature in the pathophysiology of cutaneous lesions of dermatomyositis and systemic lupus erythematosus. (2016)
  • Author(s): Nakamura K, Jinnin M, Kudo H, Inoue K, Nakayama W, Honda N, Kajihara I, Masuguchi S, Fukushima S, Ihn H.
  • Journal Title: Br J Dermatol. Volume: 5 Pages: 1030-1041
  • DOI: 10.1111/bjd.14385.
  • Peer Reviewed
• [Journal Article] Enhanced CCR9 expression levels in psoriatic skin are associated with poor clinical outcome to infliximab treatment. (2016)
  • Author(s): Koga A, Kajihara I, Yamada S, Makino K, Ichihara A, Aoi J, Makino T, Fukushima S, Jinnin M, Ihn H.
  • Journal Title: J Dermatol. Volume: 5 Pages: 522-525
  • DOI: 10.1111/1346-8138.13178.
  • Peer Reviewed
• [Journal Article] microRNA level is raised in the hair shafts of patients with dematomyositis in comparison with normal subjects and patients with scleroderma. (2016)
  • Author(s): Inoue M, Jinnin M, Wang Z, Nakamura K, Inoue K, Ichihara A, Moriya C, Sakai K, Fukushima S, Ihn H.
  • Journal Title: Int J Dermatol. Volume: 7 Pages: 786-790
  • DOI: 10.1111/ijd.12958.
  • Peer Reviewed
• [Presentation] 皮膚悪性腫瘍 up to date メラノーマバイオマーカー開発は急務である！ (2017)
  • Author(s): 福島聡
  • Organizer: 第80回日本皮膚科学会 東京支部学術大会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2017-02-11 – 2017-02-12
  • Invited
• [Presentation] Intratumoral expression levels of PD-L1, GZMA, and HLA-A along with oligoclonal T cell expansion associate with response to nivolumab (2016)
  • Author(s): Satoshi Fukushima, Hiroyuki Inoue, Jae-Hyun Park, Kazuma Kiyotani, Makda Zewde, Azusa Miyashita, Masatoshi Jinnin, Yukiko Kiniwa, Yasuhiro Fujisawa, Hiroshi Kato, Jun Asai, Kenji Yokota, Hironobu Ihn, Yusuke Nakamura
  • Organizer: 第41回日本研究皮膚科学会
  • Place of Presentation: 仙台国際センター
  • Year and Date: 2016-12-09 – 2016-12-11
• [Presentation] T cell receptor repertoire analysis in the melanoma patient with myasthenic crisis and polymyositis induced by nivolumab (2016)
  • Author(s): Satoshi Fukushima, Toshihiro Kimura, Azusa Miyashita, Jun Aoi, Masatoshi Jinnin, Hiroyuki Inoue, Kazuma Kiyotani, Jae-Hyun Park, Yusuke Nakamura, Hironobu Ihn
  • Organizer: 第45回日本免疫学会学術集会
  • Place of Presentation: 沖縄コンベンションセンター
  • Year and Date: 2016-12-05 – 2016-12-07
• [Presentation] Myasthenic crisis, polymyositis and myocarditis induced by one dose of nivolumab (2016)
  • Author(s): Satoshi Fukushima, Toshihiro Kimura, Azusa Miyashita, Jun Aoi, Masatoshi Jinnin, Hiroyuki Inoue, Kazuma Kiyotani, Jae-Hyun Park, Yusuke Nakamura, Hironobu Ihn
  • Organizer: 12th Meeting of the German-Japanese Society of Dermatology
  • Place of Presentation: Karuizawa Prince Hotel Wes
  • Year and Date: 2016-10-12 – 2016-10-14
  • Int'l Joint Research
• [Presentation] Sacran benefits impaired human skin as an artificial barrier in and on the skin (2016)
  • Author(s): Yuki Sagawa, Satoshi Fukushima, Keiichi Motoyama, Taishi Higashi Hidetoshi Arima, Moeko Doi, Shigeyoshi Momose, Takumi Tanaka, Taeko Mizutani, Hironobu Ihn, Yuri Okano
  • Organizer: IFSCC2016
  • Place of Presentation: walt disney world dolphin resort, Orlando
  • Year and Date: 2016-09-30 – 2016-10-02
  • Int'l Joint Research
• [Presentation] 乾癬に対する分子標的治療戦略 (2016)
  • Author(s): 福島聡
  • Organizer: 第４８回日本臨床分子形態学会総会・学術集会
  • Place of Presentation: くまもと県民交流館パレア
  • Year and Date: 2016-09-23 – 2016-09-24
  • Invited
• [Presentation] T cell receptor repertoire analysis in the melanoma patient with myasthenic crisis and polymyositis induced by nivolumab (2016)
  • Author(s): Satoshi Fukushima, Toshihiro Kimura, Azusa Miyashita, Jun Aoi, Masatoshi Jinnin, Hiroyuki Inoue, Kazuma Kiyotani, Jae-Hyun Park, Yusuke Nakamura, Hironobu Ihn
  • Organizer: 46th Annual ESDR Meeting 2016
  • Place of Presentation: Technical University of Munich
  • Year and Date: 2016-09-07 – 2016-09-10
  • Int'l Joint Research
• [Presentation] ニボルマブにより重症筋無力症、多発性筋炎、心筋炎を発症したメラノーマにおけるTCRレパトワ解析 (2016)
  • Author(s): 福島聡、木村俊寛、宮下梓、青井淳、神人正寿、井上博之、清谷一馬、Jae-Hyun Park、中村祐輔、尹浩信
  • Organizer: 第20回がん免疫学会
  • Place of Presentation: 大阪国際交流センター
  • Year and Date: 2016-07-27 – 2016-07-29
• [Presentation] メラノーマと樹状細胞 (2016)
  • Author(s): 福島聡
  • Organizer: 第115回日本皮膚科学会総会
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2016-06-03 – 2016-06-05
  • Invited
• [Presentation] SLN生検をreviewする (2016)
  • Author(s): 福島聡
  • Organizer: 第32回日本皮膚悪性腫瘍学会学術大会
  • Place of Presentation: 鹿児島県民交流センター
  • Year and Date: 2016-05-27 – 2016-05-28
  • Invited
• [Book] 専門医でも聞きたい皮膚科診療100の質問 《母斑・腫瘍》 56. オプジーボはメラノーマ患者を救う？ (2017)
  • Author(s): 福島聡
  • Total Pages: 1
  • Publisher: メディカルレビュー社
• [Book] 『がん免疫療法』2017年3月創刊号「Clinical Trials & Study Design」 (2017)
  • Author(s): 福島聡
  • Total Pages: 72
  • Publisher: メディカルレビュー社
• [Book] 臨床皮膚科2017年増刊号（71巻５号） 最近のトピックス2017 IV 皮膚疾患治療のポイント 《進行期悪性黒色腫の治療戦略》 (2017)
  • Author(s): 福島聡
  • Total Pages: -
  • Publisher: 医学書院
• [Book] カレントテラピー vol.34 No.4 メラノーマ ー基礎から最新薬物療法までー 6. メラノーマにおける薬物療法 ２）免疫療法 (2016)
  • Author(s): 福島聡
  • Total Pages: 93
  • Publisher: ライフメディコム