Phase I trial of retroviral-mediated transfer of the human MDR1 gene as marrow chemoprotection in patients undergoing high-dose chemotherapy and autologous stem-cell transplantation

Charles Hesdorffer, Janet Ayello, Maureen Ward, Andreas Kaubisch, Linda Vahdat, Casilda Balmaceda, Tom Garrett, Michael Fetell, Robert Reiss, Arthur Bank, Karen Antman

Research output: Contribution to journalArticle

205 Scopus citations


Purpose: Normal bone marrow cells have little or no expression of the MDR p-glycoprotein product and, therefore, are particularly susceptible to killing by MDR-sensitive drugs, such as vinca alkaloids, anthracyclines, podophyllins, and paclitaxel and its congeners. Here we report the results of a phase I clinical trial that tested the safety and efficacy of transfer of the human multiple drug resistance (MDR1, 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. Patients and Methods: Up to one third of the harvested cells of patients who were undergoing autologous bone morrow transplantation as part of a high-dose chemotherapy treatment for advanced cancer were transduced with an MDR cDNA- containing retrovirus; these transduced cells were reinfused together with unmanipulated cells after chemotherapy. Results: High-level MDR transduction of erythroid burst-forming unit (BFU-E) and colony-forming unit-granulocyte macrophage (CFU-GM) derived from transduced CD34+ cells was shown 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, posttransplantation. The cytokine-stimulated transduced cells may be out-competed in repopulation by unmanipulated normal cells that are reinfused concomitantly. The MDR retroviral supernatant that was used was shown to be free of replication-competent retrovirus (RCR) before use, and all tests of patients' samples posttransplantation were negative for RCR. In addition, no adverse events with respect to marrow engraftment or other problems related to marrow transplantation were encountered. Conclusion: These results indicate the feasibility and safety of bone marrow gene therapy with a potentially therapeutic gene, the MDR gene.

Original languageEnglish (US)
Pages (from-to)165-172
Number of pages8
JournalJournal of Clinical Oncology
Issue number1
StatePublished - Jan 1998
Externally publishedYes


ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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