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

Abstract

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.