Skip to main content
SpringerLink
Log in

Phase 1 Trial of Retroviral-Mediated Transfer of the Human MDR-1 in Patients Undergoing High-Dose Chemotherapy and Autologous Stem Cell Transplantation

  • Conference paper
Cell Therapy

Part of the book series: Keio University Symposia for Life Science and Medicine ((KEIO,volume 5))

  • 82 Accesses

Summary

Normal bone marrow cells have little or no expression of the MDR p-glycoprotein product and are, therefore, particularly susceptible to killing by MDR-sensitive drugs such as the vinca alkaloids, anthracyclines, podophyllotoxins, and taxanes. In this report of a phase 1 clinical study performed at the Columbia-Presbyterian Medical Center, we demonstrate the safety and efficacy of transfer of the human multiple drug resistance (MDR) gene into hematopoietic stem cells and progenitors in bone marrow as a means of providing resistance of these cells to the toxic effects of cancer chemotherapy. One-third of the cells harvested from patients undergoing autologous bone marrow transplantation as part of high-dose chemotherapy treatment for advanced cancer were transduced with an MDR cDNA-containing retrovirus; these transduced cells were reinfused together with unmanipulated cells following the administration of the high-dose chemotherapy. High-level MDR transduction of BFU-E and CFU-GM derived from transduced CD34+ cells was demonstrated posttransduction and prereinfusion. However, only two of the five patients showed evidence of MDR transduction of their marrow at a low level at 10 weeks and 3 weeks, respectively, post transplantation. This relatively unexpected low level of efficiency of transduction was thought to be because the unmanipulated cells, infused at the same time as the transduced cells, might compete with the cytokine-stimulated transduced cells in repopulating the marrow. The MDR retroviral supernatant used was shown to be free of replication-competent retrovirus (RCR) before use, and all tests of patient samples post transplantation were negative for RCR. In addition, no adverse events with respect to marrow engraftment or other problems related to marrow transplantation were encountered. This study does indicate the feasibility and safety of bone marrow gene therapy with a potentially therapeutic gene, the MDR gene.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 39.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 54.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 54.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Frei E III, Antman K, Teicher B, et al (1989) Bone marrow autotransplantation for solid tumors-prospects. J Clin Oncol 7: 515–526

    PubMed  Google Scholar 

  2. Hryniak W, Bush H (1984) The importance of dose intensity in chemotherapy of metastatic breast cancer. J Clin Oncol 2: 1281–1288

    Google Scholar 

  3. DeVita VT, Hubbard SM, Young RC, et al (1988) The role of chemotherapy in diffuse aggressive lymphomas. Semin Hematol 25: 2–10

    PubMed  Google Scholar 

  4. Bezwoda WR, Seymour L, Dansey RD (1995) High-dose chemotherapy with hematopoietic rescue as primary treatment for metastatic breast cancer: a randomized trial (see comments). J Clin Oncol 13: 2483–2489

    PubMed  CAS  Google Scholar 

  5. Attal M, Harousseau JL, Stoppa AM, et al (1996) A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N Engl J Med 335: 91–97

    Google Scholar 

  6. Martelli M, Vignetti M, Zinzani PL, et al (1996) High-dose chemotherapy followed by autologous bone marrow transplantation versus dexamethasone, cisplatin, and cytarabine in aggressive non-Hodgkin’s lymphoma with partial response to frontline chemotherapy: a prospective randomized Italian multicenter study. J Clin Oncol 14: 534–542

    PubMed  CAS  Google Scholar 

  7. Podda S, Ward M, Himelstein A, et al (1992) Transfer and expression of the human multiple drug resistance gene into live mice. Proc Natl Acad Sci USA 89: 9676–9680

    Article  PubMed  CAS  Google Scholar 

  8. Sorrentino BP, Brandt SJ, Bodino G, et al (1992) Selection of drug-resistant bone marrow cells in vivo after retroviral transfer of human MDR1. Science 257: 99–103

    Article  PubMed  CAS  Google Scholar 

  9. Ward M, Richardson C, Pioli P, et al (1994) Transfer and expression of the human multiple drug resistance gene in human CD34+ cells. Blood 84: 1408–1414

    PubMed  CAS  Google Scholar 

  10. Hanania E, Deisseroth AB (1994) Serial transplantation shows that early hematopoietic precursor cells are transduced by MDR-1 retroviral vector in mouse gene therapy model. Cancer Gene Ther 1: 21–25

    PubMed  CAS  Google Scholar 

  11. Ward M, Richardson C, Pioli P, et al (1996) Retroviral transfer and expression of the human MDR gene in peripheral blood progenitor cells. Clin Cancer Res 2: 873–876

    PubMed  CAS  Google Scholar 

  12. Hesdorffer C, Antman K, Bank A, et al (1994) Clinical protocol: human MDR gene transfer in patients with advanced cancer. Hum Gene Ther 5: 1151–1160

    Article  PubMed  CAS  Google Scholar 

  13. Markowitz D, Goff S, Bank A (1988) Construction and use of a safe and efficient amphotropic packaging cell line. Virology 167: 400–405

    PubMed  CAS  Google Scholar 

  14. Pastan I, Gottesman MM, Ueda K, et al (1988) A retrovirus carrying an MDR cDNA confers multidrug resistance and polarized expression of P-glycoprotein. Proc Natl Acad Sci USA 85: 4486–4490

    Article  PubMed  CAS  Google Scholar 

  15. Lebkowski JS, Schain LR, Okrongly D, et al (1992) Rapid isolation of human CD34 hematopoietic stem cells—purging of human tumor cells. Transplantation 53: 1011–1019

    Article  PubMed  CAS  Google Scholar 

  16. Okarma T, Lebkowski J, Schain L, et al (1992) The AIS selector: a new technology for stem cell purification. In: Advances in bone marrow purging and processing. Wiley-Liss, New York, pp 487–504

    Google Scholar 

  17. Berenson RJ, Bensinger WI, Kalamasz DF, et al (1992) Transplantation of stem cells enriched by immunoadsorption. Prog Clin Biol Res 377: 449–457

    PubMed  CAS  Google Scholar 

  18. Berenson RJ (1992) Transplantation of CD34+ hematopoietic precursors: clinical rationale. Transplant Proc 24: 3032–3034

    PubMed  CAS  Google Scholar 

  19. Heimfeld S, Fogarty B, McGuire K, et al (1992) Peripheral blood stem cell mobilization after stem cell factor or G-CSF treatment: rapid enrichment for stem and progenitor cells using the CEPRATE immunoaffinity separation system. Transplant Proc 24: 2818

    PubMed  CAS  Google Scholar 

  20. Noonan KE, Beck C, Holzmayer TA, et al (1990) Quantitative analysis of MDR1 (multidrug resistance) gene expression in human tumors by polymerase chain reaction. Proc Natl Acad Sci USA 87: 7160–7164

    Article  PubMed  CAS  Google Scholar 

  21. Aihara M, Aihara Y, Schmidt-Wolf G, et al (1991) A combined approach for purging multidrug-resistant leukemic cell lines in bone marrow using a monoclonal antibody and chemotherapy. Blood 77: 2079–2084

    PubMed  CAS  Google Scholar 

  22. Richardson C, Bank A (1995) Preselection of transduced murine hematopoietic stem cell populations leads to increased long-term stability and expression of the human multiple drug resistance gene. Blood 86: 2579–2589

    PubMed  CAS  Google Scholar 

  23. Lander MR, Chattopadhyay SK (1984) A Mus dunni cell line that lacks sequences closely related to endogenous murine leukemia viruses and can be infected by ectropic, amphotropic, xenotropic, and mink cell focus-forming viruses. J Virol 52: 695–698

    PubMed  CAS  Google Scholar 

  24. Bregni M, Magni M, Siena S, et al (1992) Human peripheral blood hematopoietic progenitors are optimal targets of retroviral-mediated gene transfer. Blood 80: 1418–1422

    PubMed  CAS  Google Scholar 

  25. Hanania EG, Giles RE, Kavanagh J, et al (1996) Results of MDR-1 vector modification trial indicate that granulocyte-macrophage colony-forming unit cells do not contribute to posttransplant hematopoietic recovery following intensive chemotherapy. Proc Natl Acad Sci USA 93: 15346–15351

    Article  PubMed  CAS  Google Scholar 

  26. Peters SO, Kittler EL, Ramshaw HS, et al (1996) Ex vivo expansion of murine marrow cells with interleukin-3 (IL-3), IL-6, IL-11, and stem cell factor leads to impaired engraftment in irradiated hosts. Blood 87: 30–37

    PubMed  CAS  Google Scholar 

  27. Zandstra PW, Conneally E, Piret JM, et al (1996) Normal bone marrow cells capable of generating expanded populations of LTC-IC are CD34+CD38-, require particularly high concentrations of flt3-ligand (FL) and are inhibited by excess IL-3. Blood 88: 445a

    Google Scholar 

  28. Yonemura Y, Ku H, Lyman SD, et al (1997) In vitro expansion of hematopoietic progenitors and maintenance of stem cells: comparison between flt3/flk2 ligand and kit ligand. Blood 89: 1915–1921

    PubMed  CAS  Google Scholar 

  29. Trevisan M, Yan XQ, Iscove NN (1996) Cycle intiation and colony formation in culture by murine marrow cells with long-term reconstituting potential in vivo. Blood 88: 4149–4158

    PubMed  CAS  Google Scholar 

  30. Borge OJ, Ramsfjell V, Veiby OP, et al (1996) Thromobpoietin, but not erythropoietin promotes viability and inhibits apoptosis of multipotent murine hematopoietic progenitor cells in vitro. Blood 88: 2859–2870

    PubMed  CAS  Google Scholar 

  31. Conneally E, Cashman J, Petzer AL, et al (1996) In vitro expansion of human lymphomyeloid stem cells from cord blood demonstrated using a quantitative in vivo repopulating assay. Blood 88: 628a

    Google Scholar 

  32. Conneally E, Eaves CJ, Humphries RK (1996) High efficiency gene transfer to primitive human hematopoietic stem cells capable of multilineage repopulation of immunodeficient NOD/SCID mice. Blood 88: 646a

    Google Scholar 

  33. Qin S, Ward M, Raftopoulos H, Hesdorffer C, Bank A (1998) Delayed infusion of normal hematopoietic stem cells increases marrow reconstitution of retrovirally-transduced cells. Blood 90: 118a

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Divisions of Hematology and Oncology, Department of Medicine and Genetics and Development, College of Physicians and Surgeons of Columbia University, 177 Fort Washington Avenue, New York, NY, 10032, USA

    Charles Hesdorffer, Janet Ayello, Maureen Ward, Andreas Kaubisch, Arthur Bank & Karen Antman

Authors
  1. Charles Hesdorffer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Janet Ayello
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maureen Ward
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Andreas Kaubisch
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Arthur Bank
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Karen Antman
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, 160-8582, Shinjuku-ku, Tokyo, Japan

    Yasuo Ikeda M.D., Dr. Med. Sci. (Professor) & Yutaka Hattori M.D., Dr. Med. Sci. (Professor) & 

  2. Department of Pathology, Keio University School of Medicine, 35 Shinanomachi, 160-8582, Shinjuku-ku, Tokyo, Japan

    Jun-ichi Hata M.D., Dr. Med. Sci. (Professor) (Professor)

  3. Department of Microbiology, Keio University School of Medicine, 35 Shinanomachi, 160-8582, Shinjuku-ku, Tokyo, Japan

    Shigeo Koyasu Ph.D. (Professor) (Professor)

  4. Institute for Advanced Medical Research, Keio University School of Medicine, 35 Shinanomachi, 160-8582, Shinjuku-ku, Tokyo, Japan

    Yutaka Kawakami M.D., Dr. Med. Sci. (Professor) (Professor)

Rights and permissions

Reprints and permissions

Copyright information

© 2000 Springer-Verlag Tokyo

About this paper

Cite this paper

Hesdorffer, C., Ayello, J., Ward, M., Kaubisch, A., Bank, A., Antman, K. (2000). Phase 1 Trial of Retroviral-Mediated Transfer of the Human MDR-1 in Patients Undergoing High-Dose Chemotherapy and Autologous Stem Cell Transplantation. In: Ikeda, Y., Hata, Ji., Koyasu, S., Kawakami, Y., Hattori, Y. (eds) Cell Therapy. Keio University Symposia for Life Science and Medicine, vol 5. Springer, Tokyo. https://doi.org/10.1007/978-4-431-68506-7_13

Download citation

  • DOI: https://doi.org/10.1007/978-4-431-68506-7_13

  • Publisher Name: Springer, Tokyo

  • Print ISBN: 978-4-431-68508-1

  • Online ISBN: 978-4-431-68506-7

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation