Development of CD269-CAR T cells for the adoptive immunotherapy of multiple myeloma.

• Project/Area Number: 16K18459
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Tumor therapeutics
• Research Institution: Jichi Medical University
• Principal Investigator: Uchibori Ryosuke 自治医科大学, 医学部, 講師 (20458285)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2017: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: キメラ抗原受容体 / CAR / CD269 / BCMA / 多発性骨髄腫 / 養子免疫遺伝子細胞治療 / 細胞療法 / 遺伝子治療 / 養子免疫療法 / がん免疫療法 / 造血器腫瘍

Outline of Final Research Achievements

Multiple myeloma (MM) remains in most cases an incurable disease, and new therapeutic strategies are urgently required for radical cure or continued disease control. Our purpose of this study is to verify whether treatment with CD269-specific CAR-expressing T cells can eradicate myeloma cells from bone marrow of tumor-bearing NOG mice. Firstly, we uniquely developed monoclonal antibodies against human CD269. Next, we designed and verified novel CD269-specific CAR. CD269-CAR T cells showed redirected cytolysis toward CD269-positive U266 human MM-derived cells, but not CD269-negative K562 cells. Six weeks after tumor inoculation, we injected saline, non-CAR gene-modified T cells, or CAR gene-modified T cells (GMCs) into the cardiac chamber of tumor-bearing mice. In the group of GMC injection, U266 cells were dramatically eradicated from bone marrow. We conclude that adoptive transfer of CD269-CAR T cells could be a promising option for patients with MM.

Research Products

• [Journal Article] CAR-T cell（キメラ抗原受容体発現Ｔ細胞）Therapy (2018)
  • Author(s): 内堀亮介, 小澤敬也
  • Journal Title: 医薬ジャーナル Volume: 54 Pages: 79-85
• [Journal Article] 多発性骨髄腫に対するCAR-T細胞療法の開発研究 (2017)
  • Author(s): 内堀亮介
  • Journal Title: 血液フロンティア Volume: 27 Pages: 49-56
• [Journal Article] 多発性骨髄腫に対するキメラ抗原受容体T 細胞療法の可能性 (2017)
  • Author(s): 内堀亮介
  • Journal Title: 血液内科 Volume: 74 Pages: 392-397
  • NAID: 40021144514
• [Presentation] CAR-T therapy for multiple myeloma. (2017)
  • Author(s): Uchibori R.
  • Organizer: The 23rd Annual Meeting of the Japan Society of Gene Therapy.
  • Invited
• [Presentation] CD269（BCMA）を標的とした多発性骨髄腫に対するCAR-T療法 (2017)
  • Author(s): 内堀 亮介
  • Organizer: 第23回血液科学セミナー
  • Invited
• [Presentation] CD269-CAR-T therapy for bone lesions in myeloma model mice. (2017)
  • Author(s): Uchibori R, Ohmine K, Mineno J, Takesako K, and Ozawa K.
  • Organizer: The 8th JSH International Symposium.
  • Int'l Joint Research
• [Presentation] Effect of CAR-T therapy on bone lesions in an orthotopic multiple myeloma mouse model. (2017)
  • Author(s): Uchibori R, Ohmine K, Sehara Y, Urabe M, Mizukami H, Mineno J, Takesako K, and Ozawa K.
  • Organizer: 20th Annual Meeting of the American Society of Gene & Cell Therapy.
  • Int'l Joint Research
• [Presentation] AR-T療法の基礎 (2017)
  • Author(s): 内堀 亮介
  • Organizer: 第32回悪性リンパ腫治療研究会
  • Invited
• [Presentation] Therapeutic efficacy of CD269-specific CAR T cells in an orthotopic mouse model of multiple myeloma. (2016)
  • Author(s): Ryosuke Uchibori, Takeshi Teruya, Ken Ohmine, Masashi Urabe, Yasushi Saga, Hiroaki Mizukami, Junichi Mineno, and Keiya Ozawa.
  • Organizer: 第78回日本血液学会学術集会
  • Place of Presentation: パシフィコ横浜（神奈川県、横浜市）
  • Year and Date: 2016-10-14
• [Presentation] Therapeutic efficacy of CD269-targeted CAR-modified T cells in an orthotopic mouse model of multiple myeloma. (2016)
  • Author(s): Ryosuke Uchibori, Ken Ohmine, Masashi Urabe, Hiroaki Mizukami, Junichi Mineno, and Keiya Ozawa.
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県、横浜市）
  • Year and Date: 2016-10-08
• [Presentation] Efficacy of adoptive immunotherapy with 269-CAR T cells in an orthotopic NOG mouse-human tumor xenograft model. (2016)
  • Author(s): 内堀 亮介、照屋 武志、大嶺 謙、峰野 純一、小澤 敬也
  • Organizer: 第8回血液疾患免疫療法学会
  • Place of Presentation: 北海道大学医学部学友会館（北海道、札幌市）
  • Year and Date: 2016-09-03
• [Presentation] CD269-targeted CAR-modified T cells showed promising therapeutic efficacy in an orthotopic mouse model of multiple myeloma. (2016)
  • Author(s): Ryosuke Uchibori, Takeshi Teruya, Ken Ohmine, Masashi Urabe, Yasushi Saga, Hiroaki Mizukami, Junichi Mineno, and Keiya Ozawa.
  • Organizer: 第22回日本遺伝子細胞治療学会
  • Place of Presentation: 虎ノ門ヒルズフォーラム（東京都、港区）
  • Year and Date: 2016-07-28
• [Presentation] Assessment of the efficacy and safety of CD269-specific CAR-expressing T cells using an orthotopic multiple myeloma mouse model. (2016)
  • Author(s): Ryosuke Uchibori, Takeshi Teruya, Ken Ohmine, Junichi Mineno, Kazuto Takesako, and Keiya Ozawa.
  • Organizer: The 7th JSH International Symposium
  • Place of Presentation: 淡路夢舞台（兵庫県、淡路市）
  • Year and Date: 2016-05-13
  • Int'l Joint Research
• [Presentation] CD269 (BCMA)-specific CAR-expressing T cells dramatically eradicate myeloma cells from bone marrow of an orthotopic multiple myeloma mouse model. (2016)
  • Author(s): Ryosuke Uchibori, Takeshi Teruya, Ken Ohmine, Masashi Urabe, Yasushi Saga, Hiroaki Mizukami, Junichi Mineno, Kazuto Takesako, and Keiya Ozawa.
  • Organizer: The 19th Annual Meeting of the American Society of Gene & Cell Therapy
  • Place of Presentation: Washington, D.C., USA.
  • Year and Date: 2016-05-05
  • Int'l Joint Research