Development of genetically modified iPS cell derived M1 macrophage therapy against melanoma

2020 Fiscal Year Annual Research Report

• Project/Area Number: 18K08301
• Research Institution: Kumamoto University
• Principal Investigator: 福島 聡 熊本大学, 大学院生命科学研究部(医), 教授 (50398210)
• Co-Investigator(Kenkyū-buntansha): 尹 浩信 熊本大学, 大学院生命科学研究部(医), 教授 (20282634) [Withdrawn]
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: メラノーマ / iPS細胞 / マクロファージ / がん免疫療法 / 腫瘍微小環境 / 4-1BBL / 抗原特異性 / 免疫細胞治療

Outline of Annual Research Achievements

まずB6マウスに同一の遺伝的背景を持つマウスメラノーマを播種させ、同系統のiPS細胞由来マクロファージ（iPS-MP）で治療する実験系を用いて研究を行った。IL-15、OX40、4-1BBL遺伝子改変を行なったiPS-MPは、遺伝子改変をおこなっていないiPS-MPよりも、有意に腫瘍の播種を抑制した。今年度は特にiPS-MP-41BBLの効果発現メカニズム、特に抗原特異的なT細胞に対する影響を解析した。モデル抗原として卵白アルブミン（OVA）とOVA発現マウスメラノーマ（MO4）を用いた。OVAペプチドを負荷したiPS-MP-41BBLの投与によりマウス体内でOVA特異キラーT細胞が脾臓で増加すること、さらには腫瘍内浸潤も増加することを確認した。4-1BBLがない細胞での免疫に比べて、CD8陽性かつOVAテトラマー陽性細胞は6.21%から20.89%と増加していた。このことは、iPS-MP-41BBLが抗原特異的なキラーT細胞をマウス体内で効率的に誘導できることを示している。また、in vitroでOVA特異的なT細胞の増殖をiPS-MP-41BBLが有意に増強することも確認した。
また、将来の臨床応用を目指して、B6マウスと遺伝的背景が同じB6マウス由来iPS細胞を使った治療と、MHC class Iは同じだが、MHC class II がひとつだけ違う遺伝的背景をもつE14-ES細胞から作成したMPすなわちE14-ES-MP-41BBLとその治療効果を比べた。その結果、ほぼ遜色ない効果を確認した。これは、将来iPSバンクを用いたアロ細胞治療を行うときに、他人から作成したHLAが若干不一致なiPS-MPでも治療ができる可能性を示している。このとき、各臓器を組織学的に検討したが、自己免疫現象が起きている所見はなかった。

Research Products

• [Journal Article] Existence of Staphylococcus aureus correlates with the progression of extramammary Paget's disease: potential involvement of interleukin-17 and M2-like macrophage polarization. (2021)
  • Author(s): Sakamoto R, Kajihara I, Mijiddorj T, Otsuka-Maeda S, Sawamura S, Nishimura Y, Kanemaru H, Kanazawa-Yamada S, Nakamura K, Honda N, Makino K, Aoi J, Igata T, Makino T, Masuguchi S, Fukushima S, Morinaga J, Komohara Y, Ihn H.
  • Journal Title: Eur J Dermatol. Volume: 31 Pages: 48-54
  • DOI: 10.1684/ejd.2021.3972.
  • Peer Reviewed
• [Journal Article] Immune cell therapy against disseminated melanoma by utilizing induced pluripotent stem cell-derived myeloid cell lines producing interferon-beta or interleukin-15/interleukin-15 receptor alpha (2021)
  • Author(s): Mizuhashi S, Kubo Y, Fukushima S, Kanemaru H, Nakahara S, Miyasita A, Ishibashi T, Kuriyama H, Kimura T, Masuguchi S, Zhang R, Iwama T, Nakatsura T, Uemura Y, Senju S, Ihn H.
  • Journal Title: J Dermatol Sci. Volume: - Pages: -
  • DOI: 10.1016/j.jdermsci.2021.03.005.
  • Peer Reviewed
• [Journal Article] Improved safety of induced pluripotent stem cell-derived antigen-presenting cell-based cancer immunotherapy (2021)
  • Author(s): Mashima H, Zhang R, Kobayashi T, Tsukamoto H, Liu T, Iwama T, Hagiya Y, Yamamoto M, Fukushima S, Okada S, Idiris A, Kaneko S, Nakatsura T, Ohdan H, Uemura Y.
  • Journal Title: Mol Ther Methods Clin Dev . Volume: 21 Pages: 171-179
  • DOI: 10.1016/j.omtm.2021.03.002.
  • Peer Reviewed / Open Access
• [Journal Article] Five-year survival with nivolumab in previously untreated Japanese patients with advanced or recurrent malignant melanoma (2021)
  • Author(s): Uhara H, Kiyohara Y, Uehara J, Fujisawa Y, Takenouchi T, Otsuka M, Uchi H, Fukushima S, Minami H, Hatsumichi M, Yamazaki N.
  • Journal Title: J Dermatol . Volume: 48 Pages: 592-599
  • DOI: 10.1111/1346-8138.15804.
  • Peer Reviewed
• [Journal Article] Immunotherapy with 4-1BBL-Expressing iPS Cell-Derived Myeloid Lines Amplifies Antigen-Specific T Cell Infiltration in Advanced Melanoma (2021)
  • Author(s): Kuriyama H, Fukushima S, Kimura T, Kanemaru H, Miyashita A, Okada E, Kubo Y, Nakahara S, Tokuzumi A, Nishimura Y, Kajihara I, Makino K, Aoi J, Masuguchi S, Tsukamoto H, Inozume T, Zhang R, Nakatsura T, Uemura Y, Senju S, Ihn H.
  • Journal Title: Int J Mol Sci . Volume: - Pages: -
  • DOI: 10.3390/ijms22041958.
  • Peer Reviewed / Open Access
• [Journal Article] Nucleosome assembly protein 1-like 4, a new therapeutic target for proliferation and invasion of melanoma cells (2021)
  • Author(s): Mizuhashi S, Fukushima S, Ishibashi T, Kuriyama H, Kimura T, Kanemaru H, Kajihara I, Makino K, Miyashita A, Aoi J, Kita K, Ihn H.
  • Journal Title: J Dermatol Sci . Volume: - Pages: -
  • DOI: 10.1016/j.jdermsci.2021.02.001.
  • Peer Reviewed
• [Journal Article] Concordance and Discordance Rates of V-Raf Murine Sarcoma Viral Oncogene Homolog B1 ( BRAF) V600E Status in Metastatic against Primary Lesion of Melanoma: A Meta-analysis (2020)
  • Author(s): Yokomichi H, Inozume T, Wada M, Asai J, Igaki H, Namikawa K, Hayashi A, Fukushima S, Fujimura T, Koga H, Nakamura Y, Mochizuki M, Yamagata Z.
  • Journal Title: JMA J . Volume: 3 Pages: 274-279
  • DOI: 10.31662/jmaj.2020-0016.
  • Peer Reviewed
• [Journal Article] miR-524-5p reduces the progression of the BRAF inhibitor-resistant melanoma (2020)
  • Author(s): Nguyen MT, Lin CH, Liu SM, Miyashita A, Ihn H, Lin H, Ng CH, Tsai JC, Chen MH, Tsai MS, Lin IY, Liu SC, Li LY, Fukushima S, Lu J, Ma N.
  • Journal Title: Neoplasia . Volume: 22 Pages: 789-799
  • DOI: 10.1016/j.neo.2020.10.009.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Skin microbiome in acral melanoma: Corynebacterium is associated with advanced melanoma (2020)
  • Author(s): Mizuhashi S, Kajihara I, Sawamura S, Kanemaru H, Makino K, Aoi J, Makino T, Masuguchi S, Fukushima S, Ihn H.
  • Journal Title: J Dermatol . Volume: 48 Pages: e15-e16
  • DOI: 10.1111/1346-8138.15633.
  • Peer Reviewed
• [Journal Article] Methyl-CpG binding domain protein 3: a new diagnostic marker and potential therapeutic target of melanoma (2020)
  • Author(s): Ishibashi T, Kajihara I, Mizuhashi S, Kuriyama H, Kimura T, Kanemaru H, Makino K, Miyashita A, Aoi J, Makino T, Fukushima S, Kita K, Ihn H.
  • Journal Title: Biosci Trends . Volume: 14 Pages: 390-395
  • DOI: 10.5582/bst.2020.01048.
  • Peer Reviewed / Open Access
• [Journal Article] Matrin-3 plays an important role in cell cycle and apoptosis for survival in malignant melanoma (2020)
  • Author(s): Kuriyama H, Fukushima S, Kimura T, Okada E, Ishibashi T, Mizuhashi S, Kanemaru H, Kajihara I, Makino K, Miyashita A, Aoi J, Okada S, Ihn H, Kita K.
  • Journal Title: J Dermatol Sci. Volume: 100 Pages: 110-119
  • DOI: 10.1016/j.jdermsci.2020.08.013.
  • Peer Reviewed
• [Journal Article] Single administration of avelumab induced a complete response in thyroid transcription factor 1-positive combined Merkel cell carcinoma (2020)
  • Author(s): Kanemaru H, Fukushima S, Mizukami Y, Sawamura S, Nakamura K, Honda N, Makino K, Kajihara I, Aoi J, Makino T, Kawasaki T, Kudou E, Jhono M, Ito T, Arima N, Ihn H.
  • Journal Title: J Dermatol . Volume: 47 Pages: 1317-1321.
  • DOI: 10.1111/1346-8138.15543.
  • Peer Reviewed
• [Journal Article] BATF2 expression as a novel marker for invasive phenotype in malignant melanoma (2020)
  • Author(s): Tagawa H, Kanemaru H, Kimura T, Kuriyama H, Sawamura S, Kajihara I, Miyashita A, Aoi J, Fukushima S, Ihn H.
  • Journal Title: J Dermatol . Volume: 47 Pages: e372-e373
  • DOI: 10.1111/1346-8138.15495.
  • Peer Reviewed
• [Journal Article] Serum anti-p53 autoantibodies in angiosarcoma (2020)
  • Author(s): Kiyohara M, Aoi J, Kajihara I, Otuka S, Kadomatsu T, Fukushima S, Ihn H.
  • Journal Title: J Dermatol . Volume: 47 Pages: 849-854.
  • DOI: 10.1111/1346-8138.15416.
  • Peer Reviewed
• [Journal Article] Induced pluripotent stem cell-derived myeloid cells expressing OX40 ligand amplify antigen-specific T cells in advanced melanoma (2020)
  • Author(s): Kimura T, Fukushima S, Okada E, Kuriyama H, Kanemaru H, Kadohisa-Tsuruta M, Kubo Y, Nakahara S, Tokuzumi A, Kajihara I, Makino K, Miyashita A, Aoi J, Makino T, Tsukamoto H, Nishimura Y, Inozume T, Zhang R, Uemura Y, Senju S, Ihn H.
  • Journal Title: Pigment Cell Melanoma Res . Volume: 33 Pages: 744-755
  • DOI: 10.1111/pcmr.12887.
  • Peer Reviewed
• [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: 47 Pages: e235-e237
  • DOI: 10.1111/1346-8138.15336.
  • Peer Reviewed
• [Journal Article] Case series of cutaneous T-cell lymphomas treated with bexarotene-based therapy (2020)
  • Author(s): Fujimura T, Sato Y, Tanita K, Amagai R, Shimauchi T, Ogata D, Fukushima S, Miyashita A, Fujisawa Y, Kambayashi Y, Aiba S.
  • Journal Title: J Dermatol . Volume: 47 Pages: 636-640.
  • DOI: 10.1111/1346-8138.15322.
  • Peer Reviewed
• [Journal Article] Inhibition of Endoglin Exerts Antitumor Effects through the Regulation of Non-Smad TGF-β Signaling in Angiosarcoma (2020)
  • Author(s): Sakamoto R, Kajihara I, Miyauchi H, Maeda-Otsuka S, Yamada-Kanazawa S, Sawamura S, Kanemaru H, Makino K, Aoi J, Makino T, Fukushima S, Masuzawa M, Masuzawa M, Amoh Y, Hoshina D, Abe R, Ihn H.
  • Journal Title: J Invest Dermatol . Volume: 140 Pages: 2060-2072.e6.
  • DOI: 10.1016/j.jid.2020.01.031.
  • Peer Reviewed
• [Journal Article] Non-small-cell Lung Cancer with Severe Skin Manifestations Related to Radiation Recall Dermatitis after Atezolizumab Treatment (2020)
  • Author(s): Nakashima K, Saruwatari K, Sato R, Imamura K, Kajihara I, Fukushima S, Saito T, Ishizuka S, Tamanoi D, Jodai T, Hamada S, Tomita Y, Saeki S, Ichiyasu H, Oya N, Ihn H, Sakagami T.
  • Journal Title: Intern Med . Volume: 59 Pages: 1199-1202.
  • DOI: 10.2169/internalmedicine.3937-19.
  • 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 Pages: 126-e127.
  • DOI: 10.1111/1346-8138.15198.
  • Peer Reviewed
• [Presentation] 1.Efficacy of salvage therapies after failure of anti-PD-1 monotherapy for advanced melanoma in an Asian population: A multi-institutional historical cohort study (2020)
  • Author(s): Y Teramoto, K Namikawa, Y Kiniwa, K Yoshino, S Yoshikawa, Y Nakamura, T Funakoshi, T Takenouchi, T Isei, T Maekawa, T Miyagawa, Y Fujisawa, K Yokota, T Ito, H Uhara, S Matsushita, H Doi, Y Shibayama, S Fukushima, N Yamazaki
  • Organizer: The European Society for Medical Oncology (ESMO) Virtual Congress 2020
  • Int'l Joint Research
• [Presentation] 3.Real-world efficacy of anti-PD-1 antibodies in advanced subungual melanoma: The large multicenter retrospective Japanese Acral Melanoma PD-1 (JAMP) study of 70 cases (2020)
  • Author(s): Y Nakamura, K Namikawa, K Yoshino, S Yoshikawa, H Uchi, K Goto, Y Nakamura, S Fukushima, Y Kiniwa, T Takenouchi, H Uhara, T Kawai, N Hatta, T Funakoshi, Y Teramoto, A Otsuka, J Uehara, D Ogata, S Matsushita, N Yamazaki
  • Organizer: 16TH European Association of Dermato-Oncology Congress
  • Int'l Joint Research
• [Presentation] 免疫チェックポイント阻害薬による免疫関連有害事象に対するiREACT 活動の評価 (2020)
  • Author(s): 成田さわな・久本佳奈・冨田雄介・宮本英明・吉永 佳代・森永潤・山ノ内祥訓・佐伯祥・陶山浩一・福島聡
  • Organizer: 第41回臨床薬理学会