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Development of cancer immunogene therapy with gene-modified adenoviral vector re-targeted by tumor-specific peptides

Research Project

Project/Area Number 14570964
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Hematology
Research InstitutionThe University of Tokyo

Principal Investigator

TAKAHASHI Satoshi  The University of Tokyo, The Institute of Medical Science, Lecturer, 医科学研究所, 講師 (60226834)

Co-Investigator(Kenkyū-buntansha) OOI Jun  The University of Tokyo, The Institute of Medical Science, Research Associate, 医科学研究所, 助手 (20302606)
ASANO Shigetaka  The University of Tokyo, The Institute of Medical Science, Professor, 医科学研究所, 教授 (50134614)
Project Period (FY) 2002 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2003: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2002: ¥2,200,000 (Direct Cost: ¥2,200,000)
KeywordsGene therapy / Cancer immunology / Cell therapy / Targeting / Adenovirus / CD4O ligand / Leukemia / Random peptide-presenting phage library
Research Abstract

CD4O ligand (CD40L) is a good candidate molecule for the immunotherapy of B cell malignancies including B-chronic lymphocytic leukemia (B-CLL), because it may increase the capacity of the malignant cells to present tumor antigens. However, efforts to manipulate expression of the human CD40L (hCD40L) molecule have foundered on problems associated with lack of consistent gene transfer into the malignant target cells. We have developed a new, highly reproducible method for inducing hCD40L surface expression on malignant B cells. Ten B-CLL samples were cocultured with MRC-5 fibroblasts previously transduced with an adenoviral vector encoding the hCD40Lgene. The malignant cells expressed high levels of surface hCD40L, B7-1, B7-2, and ICAM-1 after coculture. hCD40L transfer was not mediated, by membrane fusion. The transferred hCD40L was functionally intact and B-CLL cells expressing this molecule induced increased interferon-g production from autologous peripheral blood T lymphocytes. This … More approach does not use any direct gene transfer to primary leukemia cells and can readily be scaled up for prod uction of clinical B-CLL vaccines.
On the other hand, to provide cell-binding ligands for ex vivo gene therapy and B-CLL-targeting ligands for in vivo drug and gene therapy, we have selected 44 20-mer peptides from peptide-presenting phage libraries by panning against patient primary B-CLL cells. 29 of the selected peptides were assayed for cell binding. Fourteen of the selected peptides bound B-CLL, B, T, and monocyte cells, six bound only B-CLL and B cells, and one peptide bound only B cells. However, eight of the selected peptides were B-CLL specific. When peptides were tested out of the context of phage, synthetic peptide 1-5 was able to functionally re-target adenoviral vectors for increased ex vivo gene delivery to primary B-CLL cells. This work also emphasizes the importance of patient to patient tumor heterogeneity for the identification of targeting peptides and their functional application for gene therapy vector targeting. We are now planning the clinical application with these methods. Less

Report

(3 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • Research Products

    (18 results)

All Other

All Publications (18 results)

  • [Publications] Biagi E, Takahashi S, et al.: "Induction of Functional Human CD40 Ligand (hCD40L) Expression on B-Chronic Lymphocytic Leukemia Cells."Hum Gene Ther. 14. 545-559 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Ooi J, Takahashi S, et al.: "Unrelated cord blood transplantation for adult patients with advanced myelodysplastic syndrome"Blood. 101. 4711-4713 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Takahashi S, et al.: "Selection of chronic lymphocytic leukemia (CLL) binding peptides"Cancer Res. 63. 5213-5217 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Takahashi S, et al.: "Unrelated cord blood transplantation for adult patients with de novo acute myeloid leukemia."Blood. 103. 489-491 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Harata M, Takahashi S, et al.: "CD19-targeting liposomes containing imatinib efficiently kill Philadelphia chromosome-positive acute lymphoblastic leukemia cells"Blood. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Barry, M.A., Takahashi S, et al.: "Phage display of peptides. in Vector targeting strategies for therapeutic gene delivery."Wiley & Sons, Inc.New York, NY. 549-579 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Barry.M.A., Takahashi S, et al.: "Phage display of Peptides"Vector targeting strategies for therapeutic gene delivery. John Wiley & sons, Inc. New York, NY. 549-579 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Biagi E, Takahashi S, et al.: "Induction of Functional Human CD40 Ligand (hCD40L) Expression on B-Chronic Lymphocytic Leukemia Cells."Hum Gene Ther. 14. 545-559 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Ooi J, Takahashi S, et al.: "Unrelated cord blood transplantation for adult patients with advanced myelodysplastic syndrome."Blood. 101. 4711-4713 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Ooi J, Takahashi S, et al.: "Unrelated cord blood transplantation for adult patients with de novo acute myeloid leukemia."Blood. 103. 489-491 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Harata M, Takahashi S, et al.: "CD19-targeting liposomes containing imatinib efficiently kill Philadelphia chromosome-positive acute lymphoblastic leukemia cells."Blood First Edition Paper, prepublished online May 20. DOI10.1182. blood-2004-02-0588 (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Takahashi S, et al.: "Selection of chronic lymphocytic leukemia (CLL) binding peptides"Cancer Res. 63. 5213-5217 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Ooi J, Takahashi S, et al.: "Unrelated cord blood transplantation for adult patients with de novo acute myeloid leukemia."Blood. 103. 489-491 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Barry, M.A., Takahashi S, et al.: "Phage display of peptides. in Vector targeting strategies for therapeutic gene delivery.(D.T. Curiel and J.T Douglas eds.) John pp."Wiley & Sons, Inc. New York, NY. 549-579 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Biagi E, Takahashi S, et al.: "Rice L, Marini F, Andreeff M, Brenner MK, Rousseau RF. Induction of Functional Human CD4O Ligand (hCD4OL) Expression on B-Chronic I vmnhocvtic I eukemia Cells"Hum Gene Ther. (in press).

    • Related Report
      2002 Annual Research Report
  • [Publications] Ooi J, Takahashi S, et al.: "A clinical comparison of unrelated cord blood transplantation and unrelated bone marrow transplantation for adult patients with acute leukemia in complete remission"Br J Hematol. 76. 140-143 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Tomonari A, Takahashi S, et al.: "Using related donors other than genotypically HLA-matched siblings in allogeneic hematopoietic stem cell transplantation for hematological disease : a single institution exnerience in Japan"Int J Hematol. 76. 354-359 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Tomonari A., Takahashi S, et al.: "Second allogeneic hematopoietic stem cell transplantation for leukemia relapse after first allogeneic transplantation : outcome of 16 patients in a single institution"Int J Hematol. 75. 318-323 (2002)

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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