CYTOKINE THERAPY WITH GENE-TRANSFECTED CELLS - SINGLE INJECTION OF IRRADIATED GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR-TRANSDUCED CELLS ACCELERATES HEMATOPOIETIC RECOVERY AFTER CYTOTOXIC CHEMOTHERAPY IN MICE

Development of cell-based delivery systems that can release therapeuti c levels of hematopoietic growth factors into the systemic circulation would facilitate treatment of patients requiring cytokine therapy. In this study, we have investigated the potential of granulocyte-macroph age colony-stimulating factor (GM-CSF)-secreting, irradiated syngeneic murine cells to accelerate hematopoietic recovery after cytotoxic che motherapy. As a model, CMS-5 fibrosarcoma cells, were transduced with a retroviral vector containing the murine GM-CSF cDNA. Transduced cell s secreted 38 ng GM-CSF/10(6) cells in 24 hours. After irradiation, in vitro GM-CSF production initially increased up to fivefold and was me asurable far about 2 weeks. One and 2 days after injection of irradiat ed, GM-CSF-secreting CMS-5 cells (N2/CMVGM-CSF/CMS5 # 6 cells) into mi ce. GM-CSF serum levels of 405 +/- 58 pg/mL and 183 +/- 36 pg/mL were measured, respectively. Serum levels were comparable with levels detec ted 3 hours after injection of 100 ng recombinant murine GM-CSF (rmGM- CSF) subcutaneously (90 pg/mL). Injection of N2/ CMVGM-CSF/CMS5 # 6 ce lls in cyclophosphamide-treated mice was as effective in accelerating neutrophil recovery as twice daily subcutaneous injections of rmGM-CSF . These data suggest that irradiated hematopoietic growth factor-secre ting cells might offer an alternative to parenteral injections of reco mbinant cytokines in the treatment of neutropenic patients. (C) 1994 b y The American Society of Hematology.