Preclinical exploratory research and development of new boron drugs for Boron-neutron immunotherapy against melanoma

• Project/Area Number: 20K08652
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53050:Dermatology-related
• Research Institution: Shimane University (2021-2022); Okayama University (2020)
• Principal Investigator: Yamasaki Osamu 島根大学, 学術研究院医学・看護学系, 教授 (90294462)
• Co-Investigator(Kenkyū-buntansha): 道上 宏之 岡山大学, 中性子医療研究センター, 准教授 (20572499)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: BNCT / メラノーマ / 複合免疫療法 / 抗PD-1抗体 / ホウ素薬剤 / ホウ素中性子捕捉療法 / アブスコパル効果 / 悪性黒色腫 / 免疫チェックポイント阻害薬

Outline of Research at the Start

近年、進行期メラノーマに対する免疫チェックポイント阻害薬が予後の延長に寄与している。しかし奏効率は30％程度である。現在我々は、免疫療法不応例に次世代がん治療であるホウ素中性子捕捉療法（BNCT）と免疫チェックポイント阻害薬による新規複合免疫療法を計画している。
本研究はその前臨床研究として、①BNCTによる免疫増強因子に関して、メラノーマ細胞やマウスモデルを用いての検証を世界に先駆けて行い、免疫チェックポイント阻害薬投与中のメラノーマ患者において免疫増強因子の再評価を行う。さらに、②新規ホウ素薬剤を作製し、メラノーマBNCTの治療効率を高めることに挑戦する。

Outline of Final Research Achievements

Immunotherapies with immune checkpoint inhibitors are successful treatments for advanced melanoma; however, it remains important to search for improved combination therapies. Boron-neutron capture therapy (BNCT) is a cell-level local particle beam therapy in which a boron agent taken up by tumor cells is irradiated with neutrons. Tumor-targeted boron drugs are amino acid derivatives that are highly compatible with melanoma and have been successfully turned into a treatment with neutron generators. We confirmed the effectiveness of the world's first combined immunotherapy that incorporates immune checkpoint inhibitors with BNCT. Using an advanced melanoma mouse model, we report strong immunotherapeutic effects by cell-mediated immunity at the irradiation site and distant sites, in addition to the direct antitumor effects of BNCT, without damage to normal tissues.

Academic Significance and Societal Importance of the Research Achievements

メラノーマ動物モデルを用いた実験でBNCTによる免疫療法増強効果とアブスコパル効果が確認できた。BNCTが免疫チェックポイント阻害薬が奏効しない進行期メラノーマ患者の治療選択肢として期待でき、共同研究を進めている進行期メラノーマに対するBNCTの複合免疫療法の臨床研究に発展できる。メラノーマに対して研究レベルで局所療法としてBNCTが施行されているが、免疫複合療法という観点から進行期メラノーマ症例に対する新規治療法をめざすことは画期的である。さらに免疫療法との相乗効果を期待できる複合免疫療法構想は、BNCTの適応が予想される頭頸部癌や乳癌、消化器癌などへも発展が期待される。

Research Products

• [Journal Article] A case of Japanese spotted fever with asymptomatic cerebral infarction and pulmonary artery embolism (2023)
  • Author(s): Fujii Eriko、Yamasaki Osamu、Kajita Ai、Akamatsu Yuki、Kawamoto Tomoko、Miyake Tomoko、Tadokoro Koh、Takaya Yoichi、Morizane Shin
  • Journal Title: European Journal of Dermatology Volume: 33 Issue: 1 Pages: 45-47
  • DOI: 10.1684/ejd.2023.4413
  • Peer Reviewed
• [Journal Article] Buruli ulcer caused by Mycobacterium ulcerans subsp. shinshuense: A case report (2023)
  • Author(s): Fujimori Takumi、Hagiya Hideharu、Iio Koji、Yamasaki Osamu、Miyamoto Yuji、Hoshino Yoshihiko、Kakehi Ayaka、Okura Mami、Minabe Hiroshi、Yokoyama Yukika、Otsuka Fumio、Higashikage Akihito
  • Journal Title: Journal of Infection and Chemotherapy Volume: 29 Issue: 5 Pages: 523-526
  • DOI: 10.1016/j.jiac.2023.02.009
  • Peer Reviewed
• [Journal Article] Efficacy comparison between anti-PD-1 antibody monotherapy and anti-PD-1 plus anti-CTLA-4 combination therapy as first-line immunotherapy for advanced acral melanoma: A retrospective, multicenter study of 254 Japanese patients (2022)
  • Author(s): Nakamura Yasuhiro、Namikawa Kenjiro、Kiniwa Yukiko、Kato Hiroshi、Yamasaki Osamu、Yoshikawa Shusuke、Maekawa Takeo、Matsushita Shigeto、Takenouchi Tatsuya、Inozume Takashi、Nakai Yasuo、Fukushima Satoshi、et al.
  • Journal Title: European Journal of Cancer Volume: 176 Pages: 78-87
  • DOI: 10.1016/j.ejca.2022.08.030
  • Peer Reviewed
• [Journal Article] Reddish Tumour with Scar on the Right Thigh: A Quiz (2022)
  • Author(s): Fukushiro Michihito、Chinuki Yuko、Ota Masataka、Honda Sakae、Yamasaki Osamu
  • Journal Title: Acta Dermato-Venereologica Volume: 102
  • DOI: 10.2340/actadv.v102.2456
  • Peer Reviewed
• [Journal Article] Antimicrobial activity of ozenoxacin and other antimicrobials against Staphylococcus aureus strains isolated from clinical skin specimens in Japan in 2019 and 2020 (2022)
  • Author(s): Kurokawa Ichiro、Kanayama Shoji、Yamasaki Osamu
  • Journal Title: Journal of Infection and Chemotherapy Volume: 28 Issue: 12 Pages: 1693-1696
  • DOI: 10.1016/j.jiac.2022.08.014
  • Peer Reviewed
• [Journal Article] Probability scoring system of intravascular large B-cell lymphoma for the application of random skin biopsy: A?retrospective cohort study (2022)
  • Author(s): Takigawa Mikiko、Yamasaki Osamu、Nomura Hayato、Miyake Tomoko、Yanai Hiroyuki、Morizane Shin
  • Journal Title: JAAD International Volume: 9 Pages: 146-152
  • DOI: 10.1016/j.jdin.2022.09.005
  • Peer Reviewed
• [Journal Article] Complete Genome Sequence of a Hyaluronate Lyase HysA- and HysB-Producing, Methicillin-Resistant Staphylococcus aureus Sequence Type 30, Staphylococcal Cassette Chromosome mec Type IVc Strain Isolated from Furunculosis in Japan (2022)
  • Author(s): Yuma Koizumi、Junzo Hisatsune、Atsushi Toyoda、Osamu Yamasaki、Jun Kaneko、Motoyuki Sugai
  • Journal Title: Microbiology Resource Announcements Volume: 11(9) Issue: 9 Pages: 30822-30822
  • DOI: 10.1128/mra.00308-22
  • Peer Reviewed / Open Access
• [Journal Article] BRAF Immunoexpression Can Be Intralesionally Heterogeneous but BRAF V600E Mutation Status Is Intralesionally Homogeneous and Interlesionally Concordant in Melanoma (2022)
  • Author(s): Tachibana Kota、Goto Keisuke、Kukita Yoji、Honma Keiichiro、Isei Taiki、Sugihara Satoru、Taniguchi Kohei、Yamasaki Osamu
  • Journal Title: The American Journal of Dermatopathology Volume: Publish Ahead of Print Issue: 7 Pages: 478-487
  • DOI: 10.1097/dad.0000000000002146
  • Peer Reviewed
• [Journal Article] Proton beam therapy followed by pembrolizumab for giant ocular surface conjunctival malignant melanoma: A case report (2022)
  • Author(s): Matsuo T, Yamasaki O, Tanaka T, Katsui K, Waki T.
  • Journal Title: Mol Clin Oncol Volume: 16 Issue: 1 Pages: 12-12
  • DOI: 10.3892/mco.2021.2445
  • NAID: 120007178403
  • Peer Reviewed
• [Journal Article] Real-world efficacy of anti-PD-1 antibody or combined anti-PD-1 plus anti-CTLA-4 antibodies, with or without radiotherapy, in advanced mucosal melanoma patients: A retrospective, multicenter study (2021)
  • Author(s): Umeda Y, Yoshikawa S, Kiniwa Y, Maekawa T, Yamasaki O, Isei T, Matsushita S, Nomura M, Nakai Y, Fukushima S, Saito S, Takenouchi T, Tanaka R, Kato H, Otsuka A, Matsuya T, Baba N, Nagase K, Inozume T, Onuma T, Kuwatsuka Y, Fujimoto N, Kaneko T, Onishi M, Namikawa K, Yamazaki N, Nakamura Y.
  • Journal Title: Eur J Cancer Volume: 157 Pages: 361-372
  • DOI: 10.1016/j.ejca.2021.08.034
  • Peer Reviewed
• [Journal Article] TIGIT/CD155 axis mediates resistance to immunotherapy in patients with melanoma with the inflamed tumor microenvironment (2021)
  • Author(s): Kawashima S, Inozume T, Kawazu M, Ueno T, Nagasaki J, Tanji E, Honobe A, Ohnuma T, Kawamura T, Umeda Y, Nakamura Y, Kawasaki T, Kiniwa Y, Yamasaki O, Fukushima S, Ikehara Y, Mano H, Suzuki Y, Nishikawa H, Matsue H, Togashi Y.
  • Journal Title: Journal for ImmunoTherapy of Cancer Volume: 9 Issue: 11 Pages: e003134-e003134
  • DOI: 10.1136/jitc-2021-003134
  • NAID: 120007175403
  • Peer Reviewed / Open Access
• [Journal Article] Anti-PD-1 antibody monotherapy versus anti-PD-1 plus anti-CTLA-4 combination therapy as first-line immunotherapy in unresectable or metastatic mucosal melanoma: a retrospective, multicenter study of 329 Japanese cases (JMAC study). (2021)
  • Author(s): Nakamura Y, Namikawa K, Yoshikawa S, et al
  • Journal Title: ESMO Open. Volume: 6 Issue: 6 Pages: 100325-100325
  • DOI: 10.1016/j.esmoop.2021.100325
  • Peer Reviewed / Open Access
• [Journal Article] Multifunctionality of CD8+ T cells and PD-L1 expression as a biomarker of anti-PD-1 antibody efficacy in advanced melanoma. (2021)
  • Author(s): Manabe K, Yamasaki O, Nakagawa Y, Miyake T, Udono H, Morizane S.
  • Journal Title: J Dermatol, Volume: 48 Issue: 8 Pages: 1186-1192
  • DOI: 10.1111/1346-8138.15904
  • Peer Reviewed
• [Journal Article] Self-assembling A6K peptide nanotubes as a mercaptoundecahydrododecaborate (BSH) delivery system for boron neutron capture therapy (BNCT) (2021)
  • Author(s): Michiue H, Kitamatsu M, Fukunaga A, Tsuboi N, Fujimura A, Matsushita H, Igawa K, Kasai T, Kondo N, Matsui H, Furuya S.
  • Journal Title: J Control Release. Volume: 330 Pages: 788-796
  • DOI: 10.1016/j.jconrel.2020.11.001
  • Peer Reviewed / Open Access
• [Journal Article] Acute pancreatitis without abdominal pain induced by administration of nivolumab and ipilimumab (2021)
  • Author(s): Yamamoto Koichiro、Oka Kosuke、Son Reina、Honda Hiroyuki、Sakae Hiroyuki、Hasegawa Kou、Horiguchi Shigeru、Kato Hironari、Yamasaki Osamu、Otsuka Fumio
  • Journal Title: Modern Rheumatology Case Reports Volume: - Issue: 2 Pages: 1-6
  • DOI: 10.1080/24725625.2021.1899444
  • Peer Reviewed
• [Presentation] ホウ素薬剤開発の現状 ~基礎研究より橋渡し研究へ向けて～ (2020)
  • Author(s): 道上宏之
  • Organizer: 第1回量子医療研究会
  • Invited
• [Presentation] CD8 T cells multifunctionality and PD-L1 expression as a biomarker of anti-PD-1 antibodies in advanced melanoma. (2020)
  • Author(s): Manabe S, Yamasaki O, Eikawa S, Kimura Y, Nakagawa Y, Miyake T, Udono H, Morizane S.
  • Organizer: The 45th Annual Meeting of the Japanese Society for Investigative Dermatology
  • Int'l Joint Research