Novel immunogene therapy for hematopoietic malignancies

• Project/Area Number: 15390301
• 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 Ehime University, School of Medicine, Associate Professor, 医学部, 助教授 (60127917)
• Co-Investigator(Kenkyū-buntansha): YAKUSHIJIN Yoshihiro Ehime University, School of Medicine, Instructor, 医学部, 助手 (30294797) ; UCHIDA Hiroyuki Ehime University, University Hospital, Instructor, 医学部附属病院, 助手 (80359926)
• Project Period (FY): 2003 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥14,700,000 (Direct Cost: ¥14,700,000); Fiscal Year 2004: ¥6,000,000 (Direct Cost: ¥6,000,000); Fiscal Year 2003: ¥8,700,000 (Direct Cost: ¥8,700,000)
• Keywords: hematopoietic malignancies / cytotoxic T lymphocyte / WT1 / cancer vaccine / immunodefcient mice / T-cell receptor / 白血病 / 免疫療法 / パーフォリン / 骨髄腫

Research Abstract

We performed studies on immunogene therapy for hematopoietic malignanicies. The data obtained from the series of study are as follows. 1) Myeloma cells are sensitive to perforin-dependent cytotoxicity mediated by WT1-specifici cytotoxic T lymphocytes (CTLs). 2)There is a difference in the control of perforin expression between CD4^+ and CD8^+ CTLs ; that is, perforin is expressed constitutively in memory CD8^+ CTLs, but is dependent on cell activation in memory CD4^+ CTLs. 3)T-cell receptor (TCR) α and β genes obtained from an HLA-A24-restricted, WT1 peptide-specific CTL clone were lentivirally transduced to polyclonally-activated T lymphocytes. TCR gene-transduced CD4+ and CD8+ T lymphocytes showed HLA-A24-restricted and WT1-specific reactivity against leukemia cells. 4)The WT1-derived epitope recognized by HLA-DP5-restricted CD4+ T-cell clone was identified. WT1-specific CD4+ T-cell clone exerted the perforin-dependent cytotoxicity against leukemia cells. 5)Phase I clinical study of cancer peptide vaccine using WT1-derived and hTERT-derived peptides has been continued. 6) Human immune system was constructed in the novel immundeficient mice by transplantation of human hematopoietic stem cells.

Research Products

• [Journal Article] Generation of human tumor-specific, HLA class I-restricted Th1 and Tc1 cells by cell engineering with tumor peptide-specific T cell receptor genes (2005)
  • Author(s): Tsuji T, et al.
  • Journal Title: Blood (in press)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Genetic subtypes of familial hemophagocytic lymphohistiocytosis, correlations with clinical features and cytotoxic T lymphocyte/natural killer cell functions (2005)
  • Author(s): Ishii e, et al.
  • Journal Title: Blood (in press)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Genetic subtypes of familial hemophagocytic lymphohistiocytosis : correlations with clinical features and cytotoxic T lymphocyte/natural killer cell functions (2005)
  • Author(s): Ishii e, et al.
  • Journal Title: Blood (in press)
• [Journal Article] Human cord blood-and bone marrow-derived CD34^+ cells regenerate gastrointestinal epithelial cells (2004)
  • Author(s): Ishikawa F, et al.
  • Journal Title: FASEB J. 18 Pages: 1958-1960
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Identification of novel MUNC13-4 mutations in familial hemophagocytic lymphohistiocytosis and functional analysis of MUNC13-4-deficient cytotoxic T lymphocytes (2004)
  • Author(s): Yamamoto K, et al.
  • Journal Title: J.Med.Genet. 41 Pages: 763-767
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Myeloma cells are highly sensitive to granule exocytosis pathway mediated by WT1-specific cytotoxic T lymphocytes (2004)
  • Author(s): Azuma T, et al.
  • Journal Title: Clin,.Cancer Res. 10 Pages: 7402-7412
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Human cord blood- and bone marrow-derived CD34^+ cells regenerate gastrointestinal epithelial cells. (2004)
  • Author(s): Ishikawa, F., Yasukawa, M., Yoshida, S., Shimoda, K., Shimoda, S., Nakamura, K., Nagatoshi, Y., Kanemaru, T., Kawano, N., Nagafuji, K., Miyamoto, T., Fukuda, T., Okamura, J., Shultz, L.D., Harada, M.
  • Journal Title: FASEB J. 18 Pages: 1958-1960
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Identification of novel MUNC13-4 mutations in familial hemophagocytic lymphohistiocytosis and functional analysis of MUNC 13-4-deficient cytotoxic T lymphocytes. (2004)
  • Author(s): Yamamoto, K., Ishii, E., Sako, M., Ohga, S., Furuno, K., Suzuki, N., Ueda, I., Imayoshi, M., Yamamoto, S., Morimoto, A., Takada, H., Hara, T., Imashuku, S., Sasazuki, T., Yasukawa, M.
  • Journal Title: J.Med.Genet. 41 Pages: 763-767
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Myeloma cells are highly sensitive to granule exocytosis pathway mediated by WT1-specific cytotoxic T lymphocytes. (2004)
  • Author(s): Azuma, T., Otsuki, T., Kuzushima, K., Froelich, C., Fujita, S., Yasukawa, M.
  • Journal Title: Clin.Cancer Res. 10 Pages: 7402-7412
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Human cord blood- and bone marrow-derived CD34^+ cells regenerate gastrointestinal epithelial cells (2004)
  • Author(s): Ishikawa F, et al.
  • Journal Title: FASEB J. 18 Pages: 1958-1960
• [Journal Article] Myeloma cells are highly sensitive to granule exocytosis pathway mediated by WT1-specific cytotoxic T lymphocytes (2004)
  • Author(s): Azuma T, et al.
  • Journal Title: Clin.Cancer Res. 10 Pages: 7402-7412
• [Journal Article] Essential roles of perforin in antigen-specific cytotoxicity mediated by human CD4^+ T lymphocytes : analysis using the combination of hereditary perforin-deficient effector cells and Fas-deficient target cells (2003)
  • Author(s): Yanai F, et al.
  • Journal Title: J.Immunol. 170 Pages: 2205-2213
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Essential roles of perforin in antigen-specific cytotoxicity mediated by human CD4^+ T lymphocytes : analysis using the combination of hereditary perforin-deficient effector cells and Fas-deficient target cells. (2003)
  • Author(s): Yanai, F., Ishii, E., Kojima, K., Hasegawa, A., Azuma, T., Hirose, S., Suga, N., Mitsudome, A., Zaitsu, M., Ishida, Y., Shirakata, Y., Sayama, K., Hashimoto, K., Yasukawa, M.
  • Journal Title: J.Immunol. 170 Pages: 2205-2213
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Generation of human tumor-specific, HLA class I-restricted Th1 and Tc1 cells by cell engineering with tumor peptide-specific T cell receptor genes.
  • Author(s): Tsuji, T., Yasukawa, M., Matsuzaki, J., Ohkuri, T., Chamoto, K., Azuma, T., Niiya, H., Miyoshi, H., Takeshima, T., Ikeda, H., Nishimura, T.
  • Journal Title: Blood (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Genetic subtypes of familial hemophagocytic lymphohistiocytosis : correlations with clinical features and cytotoxic T lymphocyte/natural killer cell functions.
  • Author(s): Ishii, E., Ueda, I., Shirakawa, R., Yamamoto, K., Horiuchi, H., Ohga, S., Furuno, K., Morimoto, A., Imayoshi, M., Ogata, Y., Sako, M., Koike, K., Sakata, A., Takada, H., Hara, T., Imashuku, S., Sasazuki T., Yasukawa, M.
  • Journal Title: Blood (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Yamanouchi, J., Yasukawa, M., et al.: "Identification of an epitope on glycoprotein IIb-IIIa that is recognized by HLA-DRB1*0405-restricted CD4^+ T cells from a patient with ITP"J.Thromb.Haemostasis. (In press). (2004)
• [Publications] Yanai, F., Yasukawa, M., et al.: "Essential roles of perforin in antigen-specific cytotoxicity mediated by human CD4^+ T lymphocytes : analysis using the combination of hereditary perforin-deficient effector cells and Fas-deficient target cells"J.Immunol.. 170. 2205-2213 (2003)
• [Publications] Oka, Y., Yasukawa, M., et al.: "Wilms tumor gene peptide-based immunotherapy for patients with overt leukemia from myelodysplastic syndrome (MDS) or MDS with myelofibrosis"Int J Hematol.. 78. 56-61 (2003)
• [Publications] Takahashi, T., Yasukawa, M., et al.: "Valpha24+ natural killer T-cell responses against T-acute lymphoblastic leukaemia cells : implications for immunotherapy"Br.J.Haematol.. 122. 231-239 (2003)
• [Publications] Hamada, M., Yasukawa, M., et al.: "Aurora2/BTAK/STK15 is involved in cell-cycle checkpoint and cell survival of aggressive non-Hodgkin's lymphoma"Br.J.Haematol.. 121. 439-447 (2003)