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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

Cancer Gene Therapy volume 13, pages 886–895 (2006)Cite this article

Abstract

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.

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Acknowledgements

We thank the patients and their families for their contributions to this study. Vector was supplied by the National Gene Vector Laboratory (U42RR11148) with support from the NCRR and NCI, NIH. We thank the Indiana University General Clinical Research Center, Stem Cell Laboratory, Apheresis and BMT unit staff for excellent technical and clinical care. We thank S Harker, Jeanette Bailey, J Kellicut, Doug Heilman, and Daniel Koller for data management and statistical support; Jeff Bailey, Karen Pollok, Vickie Graves for the technical expertise. We also thank Drs Franklin Smith, Mary Dinauer, Jeffery Goldman, and Regina Jackaki for help in protocol development. This work was supported, in part, by the National Cancer Institute (PO1 CA75426) and by a Core Centers of Excellence in Molecular Hematology (CCEMH) grant (PHS P50DK49218). KC is supported in part by the Indiana Genomic Initiative (INGEN) created through a grant from the Lilly Endowment, Inc. MWK is supported through the Stop&Shop Pediatric Brain Tumor Program. We also thank Baxter/Nexell for supplying reagents for CD34+ cell selection and Amgen for supplying cytokines. Takara Bio (Otsu, Japan) has provided the gene Therapy Working Group with an unrestricted grant to help conduct clinical gene therapy trials. DAW may receive royalties based on ‘milestones’ set forth in a licensing agreement between Takara Bio and Indiana University.

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Author notes

  1. K Cornetta and J Croop: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA

    K Cornetta

  2. Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA

    K Cornetta & R Abonour

  3. Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA

    K Cornetta

  4. Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA

    J Croop

  5. Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, USA

    E Dropcho

  6. Department of Pathology, Indiana University School of Medicine, Indianapolis, IN, USA

    R Abonour

  7. Department of Pediatric Oncology, Dana-Farber Cancer Institute and Children's Hospital, Boston, MA, USA

    M W Kieran

  8. Department of Pediatrics, Duke University, Durham, NC, USA

    S Kreissman

  9. Division of Experimental Hematology, Cincinnati Children's Research Foundation and Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    L Reeves & D A Williams

  10. Department of Pharmacology, Indiana University School of Medicine, Indianapolis, IN, USA

    L C Erickson

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Correspondence to K Cornetta.

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Cornetta, K., Croop, J., Dropcho, E. et al. 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. Cancer Gene Ther 13, 886–895 (2006). https://doi.org/10.1038/sj.cgt.7700963

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