Development of novel gene-modified T cell therapy against chemotherapy-resistant leukemia

• Project/Area Number: 15H04858
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: Ehime University
• Principal Investigator: Yasukawa Masaki 愛媛大学, 医学系研究科, 教授 (60127917)
• Co-Investigator(Renkei-kenkyūsha): Fujiwara Hiroshi 愛媛大学, 医学部附属病院, 講師 (20398291)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000); Fiscal Year 2017: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2016: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2015: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
• Keywords: がん免疫療法 / 遺伝子改変T細胞 / CAR-T細胞 / T細胞レセプター / 白血病 / WT1 / NE-ESO1 / CD16 / がん免役療法 / 骨髄腫 / NY-ESO1 / がん免疫 / 細胞傷害性T細胞 / 遺伝子細胞治療 / ADCC / 抗体療法 / 遺伝子治療

Outline of Final Research Achievements

We performed the series of experiment in order to establish the novel gene-engineered immunotherapy targeting hematological malignancies. 1) WT1-TCR-gene-transduced CTLs exerted cytotoxicity against chemotherapy-resistant leukemia stem cells. 2) CD16-CD3ζ chimeric antigen receptor gene-modified CD8+ T cells showed strong ADCC activity in the presence of monoclonal antibody targeting malignant cells. 3) HLA-A2/NY-ESO-1157 CAR-T cells appeared to exert HLA-A2-restricted cytotoxicity against hematopoietic malignancy including myeloma cells. 4) Peripheral blood CD8 T cells showed HLA-A2-restricted cytotoxicity against tumor cells in the presence of HLA-A2/NY-ESO-1157-bispecific antibody. These data strongly suggest that immunotherapy using gene-modified CTLs can establish the cure of chemotherapy-resistant hematological malignancies.

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)
• [Int'l Joint Research] ジャクソン研究所(米国)
• [Journal Article] An unusual, CD4 and CD8 dual-positive, CD25 negative, tumor cell phenotype in a patient with adult T-cell leukemia/lymphoma (2018)
  • Author(s): Casey Nicholas、Fujiwara Hiroshi、Azuma Taichi、Murakami Yuichi、Yoshimitsu Makoto、Masamoto Izumi、Nawa Yuichiro、Yamanouchi Jun、Narumi Hiroshi、Yakushijin Yoshihiro、Hato Takaaki、Yasukawa Masaki
  • Journal Title: Leukemia & Lymphoma Volume: 印刷中 Issue: 11 Pages: 2740-2742
  • DOI: 10.1080/10428194.2018.1439168
  • Peer Reviewed / Open Access
• [Journal Article] Targeted proteomics reveals promising biomarkers of disease activity and organ involvement in antineutrophil cytoplasmic antibody-associated vasculitis (2017)
  • Author(s): Ishizaki Jun, Takemori Ayako, Suemori Koichiro, Matsumoto Takuya, Akita Yoko, Sada Ken-ei, Yuzawa Yukio, Amano Koichi, Takasaki Yoshinari, Harigai Masayoshi, Arimura Yoshihiro, Makino Hirofumi, Yasukawa Masaki, Takemori Nobuaki, Hasegawa Hitoshi
  • Journal Title: Arthritis Research & Therapy Volume: 19 Issue: 1 Pages: 218-218
  • DOI: 10.1186/s13075-017-1429-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Safety and persistence of WT1-specific T-cell receptor gene-transduced lymphocytes in patients with AML and MDS. (2017)
  • Author(s): Tawara I, Kageyama S, Miyahara Y, Fujiwara H, Nishida T, Akatsuka Y, Ikeda H, Tanimoto K, Terakura S, Murata M, Inaguma Y, Masuya M, Inoue N, Kidokoro T, Okamoto S, Tomura D, Chono H, Nukaya I, Mineno J, Naoe T, Emi N, Yasukawa M, Katayama N, Shiku H.
  • Journal Title: Blood Volume: 130 Issue: 18 Pages: 1985-1994
  • DOI: 10.1182/blood-2017-06-791202
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Efficiency and Safety of CRAC Inhibitors in Human Rheumatoid Arthritis Xenograft Models (2017)
  • Author(s): Liu Shuang、Hasegawa Hitoshi、Takemasa Erika、Suzuki Yasuyuki、Oka Keizou、Kiyoi Takeshi、Takeda Hiroyuki、Ogasawara Tomio、Sawasaki Tatsuya、Yasukawa Masaki、Maeyama Kazutaka
  • Journal Title: The Journal of Immunology Volume: 199 Issue: 5 Pages: 1584-1595
  • DOI: 10.4049/jimmunol.1700192
  • Peer Reviewed / Open Access
• [Journal Article] A novel frameshift mutation leading to inherited type I antithrombin deficiency. (2017)
  • Author(s): Mori S, Yamanouchi J, Okamoto K, Hato T, Yasukawa M
  • Journal Title: Blood Coagul Fibrinolysis Volume: 28 Issue: 2 Pages: 189-192
  • DOI: 10.1097/mbc.0000000000000555
  • Peer Reviewed / Open Access
• [Journal Article] Human tolerogenic dendritic cells generated with protein kinase C inhibitor are optimal for functional regulatory T cell induction (2016)
  • Author(s): Adnan E, Yasukawa M, et al.
  • Journal Title: Clin Immunol. Volume: 173 Pages: 96-108
  • DOI: 10.1016/j.clim.2016.09.007
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Menin plays a critical role in the regulation of the antigen-specific CD8+ T cell response upon Listeria infection (2016)
  • Author(s): Yamada T, Yasukawa M, et al.
  • Journal Title: J. Immunol. Volume: 197 Pages: 4079-4089
  • Peer Reviewed
• [Journal Article] The transcriptional repressor Gfi1 plays a critical role in the development of NKT1- and NKT2-type iNKT cells (2016)
  • Author(s): Yasuoka, T. Yasukawa M, et al.
  • Journal Title: PLoS One Volume: 11 Issue: 6 Pages: e0157395-e0157395
  • DOI: 10.1371/journal.pone.0157395
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Bach2-Batf interactions control Th2-type immune response by regulating the IL-4 amplification loop. (2016)
  • Author(s): Kuwahara M, Ise W, Ochi M, Suzuki J, Kometani K, Maruyama S, Izumoto M, Matsumoto A, Takemori N, Takemori A, Shinoda K, Nakayama T, Ohara O, Yasukawa M, Sawasaki T, Kurosaki T, Yamashita M.
  • Journal Title: Nature Communications Volume: 7 Issue: 1 Pages: 12596-12596
  • DOI: 10.1038/ncomms12596
  • Peer Reviewed / Open Access
• [Journal Article] A functionally superior second-generation vector expressing an Aurora Kinase-A-specific T-cell receptor for anti-leukaemia adoptive immunotherapy (2016)
  • Author(s): Casey, N.P., Yasukawa M, et al.
  • Journal Title: PLoS One Volume: 11 Issue: 6 Pages: e0156896-e0156896
  • DOI: 10.1371/journal.pone.0156896
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Gfi1, a transcriptional repressor, inhibits the induction of the T helper type 1 programme in activated CD4 T cells (2016)
  • Author(s): Junpei Suzuki, Saho Maruyama, Hidekazu Tamauchi, Makoto Kuwahara, Mika Horiuchi, Masumi Mizuki, Mizuki Ochi, Tatsuya Sawasaki, Jinfang Zhu, Masaki Yasukawa, Masakatsu Yamashita
  • Journal Title: Immunology Volume: 147 Issue: 4 Pages: 476-487
  • DOI: 10.1111/imm.12580
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Induction of WT1-specific human CD8+ T cells from human HSCs in HLA class I Tg NOD/SCID/IL2rgKO mice. (2016)
  • Author(s): Najima Y, Tomizawa-Murasawa M, Saito Y, Watanabe T, Ono R, Ochi T, Suzuki N, Fujiwara H, Ohara O, Shultz LD, Yasukawa M, Ishikawa F.
  • Journal Title: Blood Volume: 127(6) Issue: 6 Pages: 722-734
  • DOI: 10.1182/blood-2014-10-604777
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Development of engineered T cells expressing a chimeric CD16-CD3ζ receptor to improve the clinical efficacy of mogamulizumab therapy against adult T cell leukemia (2016)
  • Author(s): Tanaka H, Yasukawa M, et al.
  • Journal Title: Clin Cancer Res. Volume: 22 Issue: 17 Pages: 4405-4416
  • DOI: 10.1158/1078-0432.ccr-15-2714
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Development of engineered T cells expressing a chimeric CD16-CD3ζ receptor to improve the clinical efficacy of mogamulizumab therapy against adult T cell leukemia (2016)
  • Author(s): Tanaka H, Fujiwara H, Ochi F, Tanimoto K, Casey N, Okamoto S, Mineno J, Kuzushima K, Shiku H, Sugiyama T, Barrett J, Yasukawa M.
  • Journal Title: Clin Cancer Res. Volume: in press
  • Acknowledgement Compliant
• [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
• [Presentation] Development of T-Cell Therapy By Exploiting Modified Antibodies Specific for A2/NY-ESO-1 for Refractory Myeloma (2017)
  • Author(s): Masaki Maruta, Toshiki Ochi, Kazushi Tanimoto, Taichi Azuma, Hiroshi Fujiwara, and Masaki Yasukawa
  • Organizer: 59th American Society of Hematology Annual Meeting
• [Presentation] Phase 1 Clinical Trial of Adoptive Immunotherapy for Acute Myelogenous Leukemia and Myelodysplastic Syndrome, Using Gene-Modified Autologous Lymphocytes Expressing WT1-Specific T-Cell Receptor (2016)
  • Author(s): Kazushi Tanimoto, Hiroshi Fujiwara, Isao Tawara, Masahiro Masuya, Shinichi Kageyama, Tetsuya Nishida, Makoto Murata, Seitaro Terakura, Yoshiki Akatsuka, Hiroaki Ikeda, Yoshihiro Miyahara, Ikuei Nukaya, Kazutoh Takesako, Nobuhiko Emi, Naoyuki Katayama, Hiroshi Shiku, Masaki Yasukawa
  • Organizer: American Society of Hematology Annual Meeting 2016
  • Place of Presentation: San Diego, USA
  • Year and Date: 2016-12-05
  • Int'l Joint Research
• [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
• [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: https://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/
• [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/