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

Purpose: Normal bone marrow cells have little or no expression of the MDR p-glycoprotein product and, therefore, are particularly susceptibl e to killing by MDR-sensitive drugs, such as vinca alkaloids, anthracy clines, podophyllins, and paclitaxel and its congeners. Here we report the results of a phase I clinical trial that tested the safety and ef ficacy of transfer of the human multiple drug resistance (MDR1, MDR) g ene into hematopoietic stem cells and progenitors in bone marrow as a means of providing resistance of these cells to the toxic effects of c ancer chemotherapy. Patients and Methods: Up to one third of the harve sted cells of patients who were undergoing autologous bone marrow tran splantation 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 afte r chemotherapy. Results: High-level MDR transduction of erythroid burs t-forming unit (BFU-E) and colony-forming unit-granulocyte macrophage (CFU-GM) derived from transduced CD34+ cells was shown posttransductio n and prereinfusion. However, only two of the five patients showed evi dence of MDR transduction of their marrow at a low level at 10 weeks a nd 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 sup ernatant that was used was shown to be free of replication-competent r etrovirus (RCR) before use, and all tests of patients' samples posttra nsplantation were negative for RCR. In addition, no adverse events wit h respect to marrow engraftment or other problems related to marrow tr ansplantation were encountered. Conclusion: These results indicate the feasibility and safety of bone marrow gene therapy with a potentially therapeutic gene, the MDR gene. (C) 1998 by American Society of Clini cal Oncology.