Immunotherapy with human iPS cell-derived myeloid cell lines against metastatic melanoma

• Project/Area Number: 17K16345
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Dermatology
• Research Institution: Kumamoto University
• Principal Investigator: Miyashita Azusa 熊本大学, 病院, 病院教員 (20467989)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 新規免疫細胞療法 / 進行期悪性黒色腫 / iPS細胞 / 細胞増殖シグナル経路

Outline of Final Research Achievements

We developed immune cell therapy with myeloid cells derived from induced pluripotent stem cells (iPS-ML) for advanced malignant melanoma.
We evaluated the potential of mouse iPS-ML as anticancer effector cells with the use of genetically modified mouse iPS-ML, that expressed type 1 IFNs or IL-15, against peritoneally disseminated mouse malignant melanoma in allo-graft model.
We found that mouse iPS-ML expressing type 1 IFNs or IL-15 suppressed the progression of mouse melanoma.

Academic Significance and Societal Importance of the Research Achievements

手術による根治ができない悪性黒色腫（メラノーマ）に対し、抗PD-1抗体をはじめとする免疫チェックポイント阻害剤などの治療が近年注目されているが、全ての患者において効果が認められるわけではなく、新たな治療法の開発が望まれている。我々が提案するiPS細胞を用いた免疫細胞療法の腫瘍増殖抑制効果について検討した結果、マウスのメラノーマ腹膜播種モデルにおいて、腫瘍の増殖を抑制する効果が認められた。この結果は、治療に難渋するがん患者に対する治療選択肢の候補としての可能性を示唆させる、意義のある結果であると考える。

Research Products

• [Journal Article] Induced pluripotent stem cell‐derived myeloid cells expressing OX40 ligand amplify antigen‐specific T cells in advanced melanoma (2020)
  • Author(s): Kimura Toshihiro、Fukushima Satoshi、Okada Etsuko、Miyashita Azusa、Tsukamoto Hirotake、Uemura Yasushi、Senju Satoru、Ihn Hironobu
  • Journal Title: Pigment Cell & Melanoma Research Volume: - Issue: 5 Pages: 744-755
  • DOI: 10.1111/pcmr.12887
  • Peer Reviewed / Open Access
• [Journal Article] Successful treatment of occult pancreatic melanoma using BRAF/MEK inhibitors. (2020)
  • Author(s): Mizukami Y, Kanemaru H, Nakamura K, Hashigo S, Kajihara I, Miyashita A, Aoi J, Fukushima S, Honda Y, Ihn H.
  • Journal Title: J Dermatol. Volume: 47 Issue: 4
  • DOI: 10.1111/1346-8138.15198
  • Peer Reviewed / Open Access
• [Journal Article] MicroRNAs that predict the effectiveness of anti-PD-1 therapies in patients with advanced melanoma. (2020)
  • Author(s): Nakahara S, Fukushima S, Okada E, Morinaga J, Kubo Y, Tokuzumi A, Matsumoto S, Tsuruta-Kadohisa M, Kimura T, Kuriyama H, Miyashita A, Kajihara I, Jinnin M, Ihn H.
  • Journal Title: J Dermatol Sci. Volume: 97 Issue: 1 Pages: 77-79
  • DOI: 10.1016/j.jdermsci.2019.11.010
  • Peer Reviewed / Open Access
• [Journal Article] Serious disseminated intravascular coagulation associated with combination therapy of nivolumab and ipilimumab in advanced melanoma. (2020)
  • Author(s): Kuriyama H, Fukushima S, Nakahara S, Kanemaru H, Miyashita A, Aoi J, Tomita Y, Kawasaki T, Nosaka K, Ihn H.
  • Journal Title: J Dermatol. Volume: - Issue: 6
  • DOI: 10.1111/1346-8138.15336
  • Peer Reviewed / Open Access
• [Journal Article] Cytomegalovirus Enterocolitis in a Patient with Refractory Immune-Related Colitis (2020)
  • Author(s): Furuta Y, Miyamoto H, Naoe H, Shimoda M, Hinokuma Y, Miyamura T, Miyashita A, Fukushima S, Tanaka M, Sasaki Y.
  • Journal Title: Case Rep Gastroenterol. Volume: 14 Issue: 1 Pages: 103-109
  • DOI: 10.1159/000506186
  • Peer Reviewed / Open Access
• [Journal Article] Case series of cutaneous T-cell lymphomas treated with bexarotene-based therapy (2020)
  • Author(s): Fujimura Taku、Sato Yota、Tanita Kayo、Amagai Ryo、Shimauchi Takatoshi、Ogata Dai、Fukushima Satoshi、Miyashita Azusa、Fujisawa Yasuhiro、Kambayashi Yumi、Aiba Setsuya
  • Journal Title: The Journal of Dermatology Volume: - Issue: 6 Pages: 636-640
  • DOI: 10.1111/1346-8138.15322
  • Peer Reviewed / Open Access
• [Journal Article] A case of overlap syndrome (scleroderma and polymyositis) associated with the development of sudden chest pain due to myocardial damage (2019)
  • Author(s): Kaneko Akira、Kajihara Ikko、Miyashita Azusa、Ihn Hironobu
  • Journal Title: Drug Discoveries & Therapeutics Volume: 13 Issue: 5 Pages: 297-298
  • DOI: 10.5582/ddt.2019.01072
  • NAID: 130007744546
  • ISSN: 1881-7831, 1881-784X
  • Year and Date: 2019-10-31
  • Peer Reviewed / Open Access
• [Journal Article] Type I Interferon Delivery by iPSC-Derived Myeloid Cells Elicits Antitumor Immunity via XCR1+ Dendritic Cells. (2019)
  • Author(s): Tsuchiya N, Zhang R, Iwama T, Ueda N, Liu T, Tatsumi M, Sasaki Y, Shimoda R, Osako Y, Sawada Y, Kubo Y, Miyashita A, Fukushima S, Cheng Z, Nakaki R, Takubo K, Okada S, Kaneko S, Ihn H, Kaisho T, Nishimura Y, Senju S, Endo I, Nakatsura T, Uemura Y.
  • Journal Title: Cell Rep. Volume: 29 Issue: 1 Pages: 162-175
  • DOI: 10.1016/j.celrep.2019.08.086
  • Peer Reviewed / Open Access
• [Journal Article] Japanese real-world study of sequential nivolumab and ipilimumab treatment in melanoma. (2019)
  • Author(s): Tsutsumida A, Fukushima S, Yokota K, Yoshikawa S, Yamasaki O, Tanemura A, Okuyama R, Uhara H, Muto Y, Miyashita A, Akiyama M, Kaji T, Koga H, Kato J, Katayama T, Itakura E, Yamazaki N, Kiyohara Y.
  • Journal Title: J Dermatol. Volume: 46 Issue: 11 Pages: 947-955
  • DOI: 10.1111/1346-8138.15073
  • Peer Reviewed / Open Access
• [Journal Article] Bexarotene Reduces Production of CCL22 From Tumor-Associated Macrophages in Cutaneous T-Cell Lymphoma (2019)
  • Author(s): Tanita Kayo、Fujimura Taku、Sato Yota、Lyu Chunbing、Kambayashi Yumi、Ogata Dai、Fukushima Satoshi、Miyashita Azusa、Nakajima Hideki、Nakamura Motoki、Morita Akimichi、Aiba Setsuya
  • Journal Title: Frontiers in Oncology Volume: 9
  • DOI: 10.3389/fonc.2019.00907
  • Peer Reviewed / Open Access
• [Journal Article] Japanese Dermatological Association Guidelines: Outlines of guidelines for cutaneous melanoma 2019. (2019)
  • Author(s): Nakamura Y, Asai J, Igaki H, Inozume T, Namikawa K, Hayashi A, Fukushima S, Fujimura T, Ito T, Imafuku K, Tanaka R, Teramoto Y, Minagawa A, Miyagawa T, Miyashita A, Wada M, Koga H, Sugaya M.
  • Journal Title: J Dermatol. Volume: 47 Issue: 2 Pages: 89-103
  • DOI: 10.1111/1346-8138.15151
  • Peer Reviewed / Open Access
• [Journal Article] Nivolumab‐induced colitis in a patient with malignant melanoma: A case report and immunological analysis (2019)
  • Author(s): Miyashita Azusa、Fukushima Satoshi、Tsukamoto Hirotake、Itai Hisae、Miyamoto Hideaki、Nakahara Satoshi、Kubo Yosuke、Kimura Toshihiro、Kuriyama Haruka、Ihn Hironobu
  • Journal Title: The Journal of Dermatology Volume: 0000 Issue: 9 Pages: 0000-0000
  • DOI: 10.1111/1346-8138.14857
  • Peer Reviewed / Open Access
• [Journal Article] Serum cell-free DNA levels are a useful marker for extramammary Paget disease. (2019)
  • Author(s): Mijiddorj T, Kajihara I, Tasaki Y, Otsuka-Maeda S, Sakamoto R, Sawamura S, Kanazawa-Yamada S, Egashira S, Inoue K, Makino K, Miyashita A, Aoi J, Igata T, Makino T, Masuguchi S, Fukushima S, Jinnin M, Morinaga J, Ikeda T, Ihn H.
  • Journal Title: Br J Dermatol. Volume: 181 Issue: 3 Pages: 505-511
  • DOI: 10.1111/bjd.17709
  • Peer Reviewed / Open Access
• [Journal Article] Serum concentrations of HGF are correlated with response to anti-PD-1 antibody therapy in patients with metastatic melanoma. (2019)
  • Author(s): Kubo Y, Fukushima S, Inamori Y, Tsuruta M, Egashira S, Yamada-Kanazawa S, Nakahara S, Tokuzumi A, Miyashita A, Aoi J, Kajihara I, Tomita Y, Wakamatsu K, Jinnin M, Ihn H
  • Journal Title: Journal of dermatological science Volume: 93 Issue: 1 Pages: 33-10
  • DOI: 10.1016/j.jdermsci.2018.10.001
  • Peer Reviewed / Open Access
• [Journal Article] Immune checkpoint inhibitors in the onset of myasthenia gravis with hyperCKemia. (2018)
  • Author(s): Koutaro Takamatsu, Shunya Nakane, Shigeaki Suzuki, Takayuki Kosaka, Satoshi Fukushima, Toshihiro Kimura, Azusa Miyashita, Akihiro Mukaino, Shiori Yamakawa, Keisuke Watanabe, Masatoshi Jinnin, Yoshihiro Komohara, Hironobu Ihn, and Yukio Ando
  • Journal Title: Ann Clin Transl Neurol. Volume: 5 Issue: 11 Pages: 1421-1427
  • DOI: 10.1002/acn3.654
  • Peer Reviewed / Open Access
• [Journal Article] Combined Blockade of IL6 and PD-1/PD-L1 Signaling Abrogates Mutual Regulation of Their Immunosuppressive Effects in the Tumor Microenvironment (2018)
  • Author(s): Tsukamoto Hirotake、Fujieda Koji、Miyashita Azusa、Fukushima Satoshi、Ikeda Tokunori、Kubo Yosuke、Senju Satoru、Ihn Hironobu、Nishimura Yasuharu、Oshiumi Hiroyuki
  • Journal Title: Cancer Research Volume: 78 Issue: 17 Pages: 5011-5022
  • DOI: 10.1158/0008-5472.can-18-0118
  • Peer Reviewed / Open Access
• [Journal Article] Dabrafenib and trametinib combination therapy safely performed in a patient with metastatic melanoma after severe liver toxicity due to vemurafenib. (2018)
  • Author(s): Shimada S, Fukushima S, Niimori D, Miyashita A, Setoyama H, Sasaki Y, Ihn H.
  • Journal Title: The Journal of Dermatology Volume: 0 Issue: 6 Pages: 0-0
  • DOI: 10.1111/1346-8138.14206
  • Peer Reviewed / Open Access
• [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 Issue: 1 Pages: 112-114
  • DOI: 10.2340/00015555-2449
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Case report of cutaneous protothecosis caused by Prototheca wickerhamii designated as genotype 2 and current status of human protothecosis in Japan (2017)
  • Author(s): Inoue Maki、Miyashita Azusa、Noguchi Hiromitsu、Hirose Noriyuki、Nishimura Kazuko、Masuda Michiaki、Ihn Hironobu
  • Journal Title: The Journal of Dermatology Volume: 45 Issue: 1 Pages: 67-71
  • DOI: 10.1111/1346-8138.14010
  • Peer Reviewed
• [Presentation] 治療に難渋した免疫チェックポイント阻害薬による腸炎の2例 (2018)
  • Author(s): 宮下梓, 福島 聡, 宮村 智裕, 山下 智香, 宮本 英明, 尹 浩信
  • Organizer: 第34回日本皮膚悪性腫瘍学会
• [Presentation] みんなおいでよ!メラノーマ病理道場・入門編 (2018)
  • Author(s): 宮下梓
  • Organizer: 第117回日本皮膚科学会総会
  • Invited
• [Presentation] 可溶性CLA-4の免疫チェックポイント阻害薬副作用出現予測マーカーとしての可能性 (2018)
  • Author(s): 宮下梓, 福島 聡, 中原 聡, 久保 陽介, 徳澄 亜紀, 門久 美菜, 木村 俊寛, 栗山 春香, 尹 浩信
  • Organizer: 第77回日本癌学会総会
• [Presentation] Pretreatment serum CTLA-4 is a potential biomarker of a risk of immune-related adverse events in metastatic melanoma (2018)
  • Author(s): Azusa Miyashita
  • Organizer: International Investigative Dermatology
  • Int'l Joint Research
• [Presentation] がん免疫療法におけるマクロファージの可能性 (2017)
  • Author(s): 宮下 梓
  • Organizer: 第45回臨床免疫学会総会
• [Presentation] Nivolumabによる大腸炎を発症した患者における免疫学的解析 (2017)
  • Author(s): 宮下 梓、福島 聡、塚本博丈、板井久恵、藤枝浩司、西村泰治、宮本英明、尹 浩信
  • Organizer: 第21回日本がん免疫学会総会
• [Presentation] Nivolumab投与後にリウマチ性多発筋痛症を発症した1例 (2017)
  • Author(s): 宮下 梓、福島 聡、影下雄一、神人正寿、尹 浩信
  • Organizer: 第33回日本皮膚悪性腫瘍学会