Development of anti-cancer cross-talk therapy using antibody and cell therapy

• Project/Area Number: 26670467
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Hematology
• Research Institution: Ehime University
• Principal Investigator: Yasukawa M 愛媛大学, 医学(系)研究科(研究院), 教授 (60127917)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: がん免疫療法 / 細胞傷害性T細胞 / ADCC活性 / キメラ遺伝子 / CD16 / CAR-T / TCR-T / 遺伝子治療 / chimeri antigen receptor / 悪性リンパ腫 / 細胞障害性T細胞 / 抗体療法 / ADCC

Outline of Final Research Achievements

The antibody therapy against malignancies depends on antibody-dependent cell-mediated cytotoxicity (ADCC). ADCC is mediated by NK cells expressing CD16 on their cell surface; however, T cells cannot exert any ADCC activity, since they are negative for CD16 expression. In this study, we attempted to produce CD16-CD3z chimeric gene and to transduce it into activated CD8-positive T cells. CD16-CD3z T cells showed high ADCC activity in the presence of antibody in vitro. In addition, it was shown that the combination therapy of CD16-CD3z T cells and antibody against the cell surface molecule of malignant cells exerted anti-tumor activity in human tumor-transplanted immune-deficient mice.

Research Products

• [Int'l Joint Research] 米国国立衛生研究所(米国)
• [Int'l Joint Research] Princess Margaret Cancer Centre(カナダ)
• [Journal Article] Optimization of T-cell Reactivity by Exploiting TCR Chain Centricity for the Purpose of Safe and Effective Antitumor TCR Gene Therapy. (2015)
  • Author(s): Ochi T, Nakatsugawa M, Chamoto K, Tanaka S, Yamashita Y, Guo T, Fujiwara H, Yasukawa M, Butler MO, Hirano N.
  • Journal Title: Cancer Immunology Research Volume: 3(9) Issue: 9 Pages: 1070-1081
  • DOI: 10.1158/2326-6066.cir-14-0222
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Antileukemia multifunctionality of CD4(+) T cells genetically engineered by HLA class I-restricted and WT1-specific T-cell receptor gene transfer. (2015)
  • Author(s): Fujiwara H, Ochi T, Ochi F, Miyazaki Y, Asai H, Narita M, Okamoto S, Mineno J, Kuzushima K, Shiku H, Yasukawa M.
  • Journal Title: Leukemia Volume: 29(12) Issue: 12 Pages: 2393-2401
  • DOI: 10.1038/leu.2015.155
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Novel Autoantigens Associated with Lupus Nephritis. (2015)
  • Author(s): Onishi S, Adnan E, Ishizaki J, Miyazaki T, Tanaka Y, Matsumoto T, Suemori K, Shudou M, Okura T, Takeda H, Sawasaki T, Yasukawa M, Hasegawa H.
  • Journal Title: PLoS One. Volume: 10 Issue: 6 Pages: e0126564-e0126564
  • DOI: 10.1371/journal.pone.0126564
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] A novel MYH9 mutation in a patient with MYH9 disorders and platelet size-specific effect of romiplostim on macrothrombocytopenia. (2015)
  • Author(s): Yamanouchi J, Hato T, Kunishima S, Niiya T, Nakamura H, Yasukawa M
  • Journal Title: Ann Hematol Volume: 94 Issue: 9 Pages: 1599-1600
  • DOI: 10.1007/s00277-015-2416-x
  • Peer Reviewed
• [Journal Article] Antileukemia multifunctionality of CD4+ T cells genetically engineered by HLA class I-restricted and WT1-specific T-cell receptor gene transfer. (2015)
  • Author(s): Fujiwara H, Ochi T, Ochi F, Miyazaki Y, Asai H, Narita M, Okamoto S, Mineno J, Kuzushima K, Shiku H, and Yasukawa M.
  • Journal Title: Leukemia Volume: in press
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Antileukemia multifunctionality of CD4+ T cells genetically engineered by HLA class I-restricted and WT1-specific T-cell receptor gene transfer (2014)
  • Author(s): Rowan AG, Suemori K, Fujiwara H, Yasukawa M, Tanaka Y, Taylor GP, Bangham C.
  • Journal Title: Retrovirology Volume: 11 Pages: 116-116
  • Peer Reviewed / Open Access
• [Journal Article] Gene-Modified Human α/β-T Cells Expressing a Chimeric CD16-CD3ζ Receptor as Adoptively Transferable Effector Cells for Anticancer Monoclonal Antibody Therapy. (2014)
  • Author(s): Yasukawa M, et al.
  • Journal Title: Cancer Immunol Res Volume: 2 Issue: 3 Pages: 249-262
  • DOI: 10.1158/2326-6066.cir-13-0099-t
  • Peer Reviewed / Open Access
• [Journal Article] Abnormal behaviors and developmental disorder of hippocampus in zinc finger protein 521 (ZFP521) mutant mice. (2014)
  • Author(s): Ohkubo N, Matsubara E, Yamanouchi J, Akazawa R, Aoto M, Suzuki Y, Sakai I, Abe T, Kiyonari H, Matsuda S, Yasukawa M, Mitsuda N.
  • Journal Title: PLoS One Volume: 9 Issue: 3 Pages: e92848-e92848
  • DOI: 10.1371/journal.pone.0092848
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Adoptive transfer of genetically engineered WT1-specific cytotoxic T lymphocytes does not induce renal injury (2014)
  • Author(s): Asai H, Fujiwara H, Kitazawa S, Kobayashi N, Ochi T, Miyazaki Y, Ochi F, Akatsuka Y, Okamoto S, Mineno J, Kuzushima K, Ikeda H, Shiku H, Yasukawa M
  • Journal Title: J Hematol Oncol. Volume: 7 Issue: 1 Pages: 3-3
  • DOI: 10.1186/1756-8722-7-3
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Adoptive Transfer of WT1-Specific TCR Gene-Transduced Lymphocytes in Patients with Myelodysplastic Syndrome and Acute Myeloid Leukemia (2015)
  • Author(s): Isao Tawara, Masahiro Masuya, Shinichi Kageyama, Tetsuya Nishida, Seitaro Terakura, Makoto Murata, Hiroshi Fujiwara, Yoshiki Akatsuka, Hiroaki Ikeda, Yoshihiro Miyahara, Daisuke Tomura, Ikuei Nukaya, Kazutoh Takesako, Nobuhiko Emi, Masaki Yasukawa, Naoyuki Katayama, Hiroshi Shiku
  • Organizer: American Society of Hematology 2015 Annual Meeting
  • Place of Presentation: 米国 オーランド
  • Year and Date: 2015-12-04
  • Int'l Joint Research
• [Presentation] Immunotherapy with Chimeric Antigen Receptor Targeting Intracellular WT1 Gene Product Complexed with HLA-a*24:02 Molecule (2015)
  • Author(s): Hiroaki Ikeda, Yasushi Akahori, Motohiro Yoneyama, Yuki Orito, Yoshihiro Miyahara, Yasunori Amaishi, Sachiko Okamoto, Junichi Mineno, Kazutoh Takesako, Hiroshi Fujiwara, Masaki Yasukawa, Hiroshi Shiku
  • Organizer: American Society of Hematology 2015 Annual Meeting
  • Place of Presentation: 米国 オーランド
  • Year and Date: 2015-12-04
  • Int'l Joint Research
• [Presentation] Targeting Aurora Kinase with a Superior T-Cell Receptor Gene-Transfer Vector (2015)
  • Author(s): Nicholas Casey, Hiroshi Fujiwara, Kazushi Tanimoto, Sachiko Okamoto, Junichi Mineno, Kiyotaka Kuzushima, Hiroshi Shiku, Masaki Yasukawa
  • Organizer: American Society of Hematology 2015 Annual Meeting
  • Place of Presentation: 米国 オーランド
  • Year and Date: 2015-12-04
  • Int'l Joint Research
• [Presentation] Activation Status of Integrin αIIbβ3 in Essential Thrombocythemia with Calreticulin Mutation (2014)
  • Author(s): Jun Yamanouchi , Takaaki Hato, Etsuko Matsubara, Taichi Azuma, Hideyuki Nakanishi, Hiroshi Fujiwara, Yoshihiro Yakushijin, and Masaki Yasukawa
  • Organizer: 56th ASH Annual Meeting
  • Place of Presentation: San Francisco
  • Year and Date: 2014-12-06
• [Presentation] Concomitant Administration of Gene-Modified T Cells Expressing a Chimeric CD16-CD3ζ Receptor with Mogamulizmab Synergistically Suppresses Adult T Cell Leukemia Cells in Vivo (2014)
  • Author(s): Kazushi Tanimoto , Hiroshi Fujiwara, Hiroki Tanaka, Fumihiro Ochi , Hiroaki Asai, Sachiko Okamoto, JunichiMineno , Kiyotaka Kuzushima, Hiroshi Shiku, John Barrett, and Masaki Yasukawa
  • Organizer: 56th ASH Annual Meeting
  • Place of Presentation: San Francisco
  • Year and Date: 2014-12-05
• [Remarks] 愛媛大学大学院医学系研究科血液・免疫・感染症内科学講座
  • URL: http://www.m.ehime-u.ac.jp/school/int.med1/
• [Remarks] 愛媛大学大学院医学系研究科血液・免疫・感染症内科学
  • URL: http://www.m.ehime-u.ac.jp/school/int.med1/