TY - JOUR
T1 - 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
AU - Hesdorffer, Charles
AU - Ayello, Janet
AU - Ward, Maureen
AU - Kaubisch, Andreas
AU - Vahdat, Linda
AU - Balmaceda, Casilda
AU - Garrett, Tom
AU - Fetell, Michael
AU - Reiss, Robert
AU - Bank, Arthur
AU - Antman, Karen
PY - 1998/1
Y1 - 1998/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0031972859&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0031972859&partnerID=8YFLogxK
U2 - 10.1200/JCO.1998.16.1.165
DO - 10.1200/JCO.1998.16.1.165
M3 - Article
C2 - 9440739
AN - SCOPUS:0031972859
SN - 0732-183X
VL - 16
SP - 165
EP - 172
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 1
ER -