A pilot study of dose-intensified procarbazine, CCNU, vincristine for poor prognosis brain tumors utilizing fibronectin-assisted, retroviral-mediated modification of CD34+ peripheral blood cells with O6-methylguanine DNA methyltransferase.
Administration of chemotherapy is often limited by myelosuppression. Expression of drug-resistance genes in hematopoietic cells has been proposed as a means to decrease the toxicity of cytotoxic agents. In this pilot study, we utilized a retroviral vector expressing methylguanine DNA methyltransferase (MGMT) to transduce hematopoietic progenitors, which were subsequently used in the setting of alkylator therapy (procarbazine, CCNU, vincristine (PCV)) for poor prognosis brain tumors. Granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood progenitor cells were collected by apheresis and enriched for CD34+ expression. Nine subjects were infused with CD34+-enriched cells treated in a transduction procedure involving a 4-day exposure to cytokines with vector exposure on days 3 and 4. No major adverse event was related to the gene therapy procedure. Importantly, the engraftment kinetics of the treated product was similar to unmanipulated peripheral blood stem cells, suggesting that the ex vivo manipulation did not significantly reduce engrafting progenitor cell function. Gene-transduced cells were detected in all subjects. Although the level and duration was limited, patients receiving cells transduced using fibronectin 'preloaded' with virus supernatant appeared to show improved in vivo marking frequency. These findings demonstrate the feasibility and safety of utilizing MGMT-transduced CD34+ peripheral blood progenitor cells in the setting of chemotherapy.
Cornetta
K
K
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, 46202, USA. kcornett@iupui.edu
Croop
J
J
Dropcho
E
E
Abonour
R
R
Kieran
M W
MW
Kreissman
S
S
Reeves
L
L
Erickson
L C
LC
Williams
D A
DA
D000293:Adolescent; D000328:Adult; D018952:Antigens, CD34 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000628:therapy*; D003114:Colony-Forming Units Assay; D017931:DNA Primers; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics* / Q000378:metabolism; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D008130:Lomustine / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics* / Q000378:metabolism; D036102:Peripheral Blood Stem Cell Transplantation / Q000379:methods; D010865:Pilot Projects; D016133:Polymerase Chain Reaction; D011344:Procarbazine / Q000008:administration & dosage / Q000627:therapeutic use*; D012190:Retroviridae / Q000235:genetics; D014161:Transduction, Genetic / Q000379:methods; D014750:Vincristine / Q000008:administration & dosage / Q000627:therapeutic use*
D018952:Antigens, CD34; D000970:Antineoplastic Agents; D017931:DNA Primers; D005353:Fibronectins; D016179:Granulocyte Colony-Stimulating Factor; D011344:Procarbazine; D014750:Vincristine; D008130:Lomustine; D019853:O(6)-Methylguanine-DNA Methyltransferase