Development of Induced pluripotent stem cell-derived macrophages expressing OX40 ligand therapy

• Project/Area Number: 20K22850
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0901:Oncology and related fields
• Research Institution: Kumamoto University
• Principal Investigator: Kimura Toshihiro 熊本大学, 病院, 診療助手 (40879904)
• Project Period (FY): 2020-09-11 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: メラノーマ / iPS-ML / OX40 / OX40L / 悪性黒色腫 / がん免疫療法

Outline of Research at the Start

不死化したiPS細胞由来ミエロイドライン(iPS-ML)に遺伝子改変を加えることで様々な免疫調整機能を持たせた治療細胞を作成することができる。我々はこのiPS-MLに免疫チェックポイントのアクセル分子であるOX40Lを導入することで、マウスメラノーマに対する治療効果が増強されることをすでに確認している。臨床応用に向けたさらなる効果増強を目指し免疫チェックポイント阻害薬との併用について検討し、そのメカニズム解析を行う。

Outline of Final Research Achievements

We have established an immune cell therapy with immortalized myeloid cell lines derived from induced pluripotent stem (iPS) cells (iPS-ML), and OX40L-expressing iPS-ML, (iPS-ML-OX40L). However, the tumorigenicity is a matter of concern. Therefore, we performed the experiments mimic allogenic situations. As a result, there was no difference in therapeutic effects between syngeneic and allogenic environments.
These results suggest that allogenic immune cell therapy could show equivalent anticancer effects and these cells will be removed immunologically in long view, therefore iPS-ML therapy will become more safe.
In future, we want to show the efficacy of iPS-ML-OX40L and immune checkpoint inhibitor combination therapy.

Academic Significance and Societal Importance of the Research Achievements

抗PD-1抗体を始めとした免疫チェックポイント阻害薬(ICI)の有効性が明らかになったが、日本人に多いとされる末端黒子型のメラノーマではその効果は限定的であるため本邦での進行期メラノーマ診療はいまだに難渋しているのが現状である。併用が期待される従来の細胞移入療法はその培養の困難さやコストの観点から一般病院での普及は非現実的である。
iPS細胞をソースとした細胞移入療法がICIの効果を増幅できれば、将来的にはバンク等から事前に各種HLAのiPS-MLを大量に作成しておくことで速やかにクオリティーの保証された細胞を供給することができるため、より広く普及しやすい細胞移入療法になることが期待できる。

Research Products

• [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: 22(4) Issue: 4 Pages: 1958-1958
  • DOI: 10.3390/ijms22041958
  • Peer Reviewed / Open Access
• [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: - Issue: 2 Pages: 133-136
  • DOI: 10.1016/j.jdermsci.2021.03.005
  • Peer Reviewed
• [Journal Article] Liquid biopsy-based analysis by ddPCR and CAPP-Seq in melanoma patients (2021)
  • Author(s): Akira Kaneko, Hisashi Kanemaru, Ikko Kajihara, Tselmeg Mijiddorj, Hitomi Miyauchi, Haruka Kuriyama, Toshihiro Kimura, Soichiro Sawamura, Katsunari Makino, Azusa Miyashita, Jun Aoi, Takamitsu Makino, Shinichi Masuguchi, Satoshi Fukushima, Hironobu Ihn
  • Journal Title: Journal of Dermatological Science Volume: 102 Issue: 3 Pages: 158-166
  • DOI: 10.1016/j.jdermsci.2021.04.006
  • Peer Reviewed
• [Journal Article] Amelanotic melanoma of the nail apparatus complicated with digital mucous cyst (2021)
  • Author(s): Takei Itsuki、Sawamura Soichiro、Kimura Toshihiro、Makino Takamitsu、Aoi Jun、Kajihara Ikko、Nishimura Yuki、Igata Toshikatsu、Masuguchi Shinichi、Fukushima Satoshi
  • Journal Title: Australasian Journal of Dermatology Volume: 63 Issue: 1
  • DOI: 10.1111/ajd.13679
  • Peer Reviewed
• [Journal Article] A mechanism of cooling hot tumors: Lactate attenuates inflammation in dendritic cells (2021)
  • Author(s): Hisashi Kanemaru, Yukari Mizukami, Akira Kaneko, Hidemi Tagawa, Toshihiro Kimura, Haruka Kuriyama, Soichiro Sawamura, Ikko Kajihara, Katsunari Makino, Azusa Miyashita, Jun Aoi, Takamitsu Makino, Shinichi Masuguchi, Satoshi Fukushima, Hironobu Ihn
  • Journal Title: iScience Volume: 24 Issue: 9 Pages: 103067-103067
  • DOI: 10.1016/j.isci.2021.103067
  • Peer Reviewed / Open Access
• [Journal Article] Methyl-CpG binding domain protein 3: a new diagnostic marker and potential therapeutic target of melanoma (2020)
  • Author(s): Takayuki Ishibashi, Ikko Kajihara, Satoru Mizuhashi, Haruka Kuriyama, Toshihiro Kimura, Hisashi Kanemaru, Katsunari Makino, Azusa Miyashita, Jun Aoi, Takamitsu Makino, Satoshi Fukushima, Kanako Kita, Hironobu Ihn
  • Journal Title: BioScience Trends Volume: 14 Issue: 5 Pages: 390-395
  • DOI: 10.5582/bst.2020.01048
  • NAID: 130007935965
  • ISSN: 1881-7815, 1881-7823
  • Year and Date: 2020-10-31
  • Peer Reviewed / Open Access
• [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] BATF2 expression as a novel marker for invasive phenotype in malignant melanoma (2020)
  • Author(s): Hidemi Tagawa, Hisashi Kanemaru, Toshihiro Kimura, Haruka Kuriyama, Soichiro Sawamura, Ikko Kajihara, Azusa Miyashita, Jun Aoi, Satoshi Fukushima, Hironobu Ihn
  • Journal Title: The Journal of Dermatology Volume: 47(10) Issue: 10 Pages: 372-373
  • DOI: 10.1111/1346-8138.15495
  • Peer Reviewed
• [Journal Article] Matrin-3 plays an important role in cell cycle and apoptosis for survival in malignant melanoma (2020)
  • Author(s): Haruka Kuriyama, Satoshi Fukushima, Toshihiro Kimura, Etsuko Okada, Takayuki Ishibashi, Satoru Mizuhashi, Hisashi Kanemaru, Ikko Kajihara, Katsunari Makino, Azusa Miyashita, Jun Aoi, Seiji Okada, Hironobu Ihn, Kanako Kita
  • Journal Title: Journal of Dermatological Science Volume: 100(2) Issue: 2 Pages: 110-119
  • DOI: 10.1016/j.jdermsci.2020.08.013
  • Peer Reviewed
• [Presentation] IPS cell-derived myeloid cells expressing OX40 ligand amplify tumor-infiltrating T cells in advanced melanoma (2021)
  • Author(s): Toshihiro Kimura
  • Organizer: The 46th Annual Meeting of the Japanese Society for Investigative Dermatology.
  • Int'l Joint Research
• [Presentation] 悪性黒色腫に対するiPS細胞由来OX40L導入マクロファージ療法の開発 (2020)
  • Author(s): 木村 俊寛
  • Organizer: 第24回日本がん免疫学会総会