Development of a novel cancer therapy using soluble T-cell receptor

• Project/Area Number: 23659489
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Hematology
• Research Institution: Ehime University
• Principal Investigator: YASUKAWA Masaki 愛媛大学, 大学院・医学系研究科, 教授 (60127917)
• Project Period (FY): 2011 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2011: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 免疫療法 / 遺伝子治療 / 細胞傷害性T細胞 / T細胞レセプター / 白血病 / 細胞障害性Ｔ細胞 / Ｔ細胞レセプター / がん免疫療法 / WT1 / Aurora-A kinase

Research Abstract

In this study, we attempted to establish a novel immunotherapyfor cancer using tumor antigen-specific soluble T-cell receptor (TCR). The data obtained from the series of experiments are follows.1) WT1, hTERT, and Aurora-A kinase-derived peptide-specific cytotoxic T cell (CTL) clones were established.2) TCR genes were isolated from these CTL clones.3) A novel retrovirus vector expressing TCR genes and inhibiting expression of endogenous TCR has been developed.4) WT1-specific hTERT-specific, and Aurora-A kinase-specific TCR gene-transduced T cells showed antigen-specific cytotoxicity and exerted anti-leukemia effects in vitro and in vivo.Now, we areattempting to produce WT1-specific soluble TCR molecules.

Research Products

• [Journal Article] Adoptive transfer of genetically modified Wilms' tumor 1-specific T cells in a novel malignant skull base meningioma model (2013)
  • Author(s): Iwami K, Natsume A, Ohno M, Ikeda H, Mineno J, Nukaya I, Okamoto S, Fujiwara H, Yasukawa M, Shiku H, Wakabayashi T
  • Journal Title: Neuro Oncol Volume: Epub ahead of print
  • Peer Reviewed
• [Journal Article] Co-introduced functional CCR2 potentiates in vivo anti-lung cancer func tionality mediated by T cells double gene-modified to express WT1-specific T-cell receptor. (2013)
  • Author(s): Yasukawa M, et al.
  • Journal Title: PLoS One Volume: 10 Issue: 2 Pages: e56820-e56820
  • DOI: 10.1371/journal.pone.0056820
  • Peer Reviewed
• [Journal Article] Novel causative and neutral mutations in a patient with protein C deficiency (2013)
  • Author(s): Yamanouchi J et al.
  • Journal Title: Thrombosis Research Volume: in press Issue: 5 Pages: 466-468
  • DOI: 10.1016/j.thromres.2013.01.021
  • Peer Reviewed
• [Journal Article] Adoptive transfer of genetically modified Wilms' tumor 1-specific T cells in a novel malignant skull base meningioma model. (2013)
  • Author(s): Iwami K, et al.
  • Journal Title: Neuro Oncol. Volume: in press
  • Peer Reviewed
• [Journal Article] Novel causative and neutral mutations in a patient with protein C deficiency. (2013)
  • Author(s): Yamanouchi J, et al.
  • Journal Title: Thromb Res. Volume: in press
  • Peer Reviewed
• [Journal Article] A promising vector for TCR gene therapy: differential effect of siRNA, 2A peptide, and disulfide bond on the introduced TCR expression. (2012)
  • Author(s): Okamoto S, et al.
  • Journal Title: Mol Ther Nucleic Acids. Volume: 18 Pages: e63-e63
  • DOI: 10.1038/mtna.2012.52
  • Peer Reviewed
• [Journal Article] HLA-restricted presentation of WT1 tumor antigen in B-lymphoblastoid cell lines established using a maxi-EBV system. (2012)
  • Author(s): Kanda, T, et al.
  • Journal Title: Cancer Gene Ther. Volume: 19 Issue: 8 Pages: 566-571
  • DOI: 10.1038/cgt.2012.34
  • Peer Reviewed
• [Journal Article] The role of activation-induced cytidine deaminase (AID/AICDA) in the progression of follicular lymphoma (2012)
  • Author(s): Shikata H, Yasukawa M, et al
  • Journal Title: Cancer Sci Volume: 103 Issue: 3 Pages: 415-421
  • DOI: 10.1111/j.1349-7006.2011.02186.x
  • Peer Reviewed
• [Journal Article] Aurora kinase A-specific T-cell receptor gene transfer redirects T-lymphocytes to display effective anti-leukemia reactivity (2012)
  • Author(s): Kozo Nagai, et al
  • Journal Title: Blood Volume: 119(2) Issue: 2 Pages: 368-76
  • DOI: 10.1182/blood-2011-06-360354
  • Peer Reviewed
• [Journal Article] Lysophosphatidylcholine enhances the suppressive function of human naturally occurring regulatory T cells through TGF-β production (2011)
  • Author(s): Hasegawa H, et al
  • Journal Title: Biochem.Biophys.Res.Commun. Volume: 415 Issue: 3 Pages: 526-531
  • DOI: 10.1016/j.bbrc.2011.10.119
  • Peer Reviewed
• [Journal Article] A new four-way variant t(5;17;15;20)(q33;q12;q22;q11.2) in acute promyelocytic leukemia (2011)
  • Author(s): Yamanouchi, J., Hato, T., Niiya, T., Miyoshi, K., Azuma, T., Sakai, I. and Yasukawa, M.
  • Journal Title: Int J Hematol Volume: 94 Issue: 4 Pages: 395-398
  • DOI: 10.1007/s12185-011-0929-1
  • NAID: 10030265460
  • Peer Reviewed
• [Journal Article] Requisite considerations for successful adoptive immunotherapy with engineered T-lymphocytes using tumor antigen-specific T-cell receptor gene transfer (2011)
  • Author(s): Ochi T, et al
  • Journal Title: Expert Opin Biol Ther Volume: 11(6) Issue: 6 Pages: 699-713
  • DOI: 10.1517/14712598.2011.566853
  • Peer Reviewed
• [Journal Article] Novel adoptive T-cell immunotherapy using a WT1-specific TCR vector encoding silencers for endogenous TCRs shows marked anti-leukemia reactivity and safety (2011)
  • Author(s): Ochi T, et al
  • Journal Title: Blood Volume: 118(6) Issue: 6 Pages: 1495-503
  • DOI: 10.1182/blood-2011-02-337089
  • Peer Reviewed
• [Journal Article] Gemcitabine enhances Wilms' tumor gene WT1 expression and sensitizes human pancreatic cancer cells with WT1-specific T-cell-mediated antitumor immune response (2011)
  • Author(s): Takahara A, et al
  • Journal Title: Cancer Immunol Immunother Volume: 60(9) Issue: 9 Pages: 1289-97
  • DOI: 10.1007/s00262-011-1033-3
  • Peer Reviewed
• [Journal Article] Feasibility of gene-immunotherapy using WT1-specific T-cell receptor gene transfer for infant acute lymphoblastic leukemia with MLL gene rearrangement (2011)
  • Author(s): Nagai K, et al
  • Journal Title: Blood Cancer Journal Volume: 1:e10 Issue: 3 Pages: e10-e10
  • DOI: 10.1038/bcj.2011.8
  • Peer Reviewed
• [Journal Article] Adoptive T-cell immunotherapy using T-cell receptor gene transfer: aiming at a cure for cancer (2011)
  • Author(s): Yasukawa, M., Ochi, T, and Fujiwara, H.
  • Journal Title: Immunotherapy Volume: 3 Issue: 2 Pages: 135-140
  • DOI: 10.2217/imt.10.103
  • Peer Reviewed
• [Journal Article] Vasodilator-stimulated phosphoprotein (VASP) phosphorylation assay for platelet response to cilostazol (2011)
  • Author(s): Yamanouchi J, et al
  • Journal Title: Platelets Volume: 22(2) Issue: 2 Pages: 135-42
  • DOI: 10.3109/09537104.2010.525976
  • Peer Reviewed
• [Journal Article] Activation of T-cell receptor signaling in peripheral T-cell lymphoma cells plays an important role in the development of lymphoma-associated hemophagocytosis (2011)
  • Author(s): An, J., Fujiwara, H., Suemori, K., Niiya, T., Azuma, T., Tanimoto, K., Ochi, T., Akatsuka, Y., Mineno, J., Ozawa, H., Ishikawa, F., Kuzushima, K. and Yasukawa, M.
  • Journal Title: Int. J. Hemattol. Volume: 93 Issue: 2 Pages: 176-185
  • DOI: 10.1007/s12185-010-0758-7
  • NAID: 10029533085
  • Peer Reviewed
• [Journal Article] Lysophosphatidylcholine enhances the suppressive function of human naturally occurring regulatory T cells through TGF-β production (2011)
  • Author(s): Hasegawa H, Yasukawa M, et al.
  • Journal Title: Biochem Biophys Res Commun. Volume: 415 Pages: 526-531
  • Peer Reviewed
• [Journal Article] Novel adoptive T-cell immunotherapy using a WT1-specific TCR vector encoding silencers for endogenous TCRs shows marked anti-leukemia reactivity and safety. (2011)
  • Author(s): Ochi T, Yasukawa M, et al.
  • Journal Title: Blood Volume: 118 Pages: 1495-1503
  • Peer Reviewed
• [Journal Article] Gemcitabine enhances Wilms’ tumor gene WT1 expression and sensitizes human pancreatic cancer cells with WT1-specific T-cell-mediated antitumor immune response. (2011)
  • Author(s): Takahara A, Yasukawa M, et al.
  • Journal Title: Cancer Immunol. Immunother. Volume: 60 Pages: 1289-1297
  • Peer Reviewed
• [Journal Article] Feasibility of gene-immunotherapy using WT1-specific T-cell receptor gene transfer for infant acute lymphoblastic leukemia with MLL gene rearrangement. (2011)
  • Author(s): Nagai K, Yasukawa M, et al.
  • Journal Title: Blood Cancer J. Volume: 1
  • Peer Reviewed
• [Journal Article] Activation of T-cell receptor signaling in peripheral T-cell lymphoma cells plays an important role in the development of lymphoma-associated hemophagocytosis. (2011)
  • Author(s): An J, Yasukawa M, et al.
  • Journal Title: Int. J. Hemattol. Volume: 93 Pages: 176-185
  • NAID: 10029533085
  • Peer Reviewed
• [Presentation] Human Telomerase Reverse Transcriptase-Specific T-Cell Receptor Gene Transfer Redirects T-Lymphocytes to Exert Effective Antitumor Reactivity Against Adult T-Cell Leukemia (2011)
  • Author(s): Miyazaki Y, Yasukawa M, et al.
  • Organizer: 53rd Annual Meeting of American Society of Hematology
  • Place of Presentation: San Diego, U.S.A.
• [Presentation] Forced Expression of CC Chemokine Receptor 2 Enhances Anti-Cancer Reactivity Mediated by T Lymphocytes Beforehand Redirected Toward WT1 Inside the Tumor Microenvironment (2011)
  • Author(s): Asai A, Yasukawa M, et al.
  • Organizer: 53rd Annual Meeting of American Society of Hematology
  • Place of Presentation: San Diego, U.S.A.
• [Presentation] Redirected CD4+ T Cells Using WT1-Specific T-Cell Receptor Gene Transfer Can Supply Multifactorial Help to Enhance the Anti-Leukemia Reactivity Mediated by Similarly Redirected CD8+ T Cells Using the Identical Gene Transfer (2011)
  • Author(s): Ochi T, Yasukawa M, et al.
  • Organizer: 53rd Annual Meeting of American Society of Hematology
  • Place of Presentation: San Diego, U.S.A.
• [Remarks]
  • URL: http://www.m.ehime-u.ac.jp/school/int.med1/
• [Remarks]
  • URL: http://www.m.ehime-u.ac.jp/school/int.med1/