Cytokines, GM-CSF and IFNγ administered by priming and post-chemotherapy cycling in recurrent ovarian cancer patients receiving carboplatin

Background: Monocyte/macrophages (MO/MA), a polymorphic population of innate immune cells, have the potential to mediate antitumor effects, and may also contribute to protumor effects. A priming and post-chemotherapy schedule of the myeloid cell mobilizing and immune stimulatory growth factor, granulocyte monocyte stimulating factor (GM-CSF, Leukine(R)) and the MO/MA activating cytokine recombinant interferon gamma 1b (rIFN-gamma 1b, Actimmune(R)) has been developed. The pre- and post-chemotherapy design is based upon known in vivo kinetics and immune modulatory effects of these molecules. Carboplatin (Paraplatin(R)) was selected as the cornerstone of treatment of epithelial ovarian cancer (EOC). Methods: We studied hematopoietic and immunologic effects of GM-CSF and rIFN-gamma 1b before and after carboplatin in patients with recurrent EOC. Potentially chemotherapy-sensitive patients with recurrent measurable tumors received subcutaneous GM-CSF (starting at 400 mu g/day) for 7 days plus subcutaneous rIFN-gamma 1b (100 mu g) on days 5 and 7, before and after intravenous carboplatin (area under the curve of 5). We performed standard hematologic assessment and monitored monocyte (MO), dendritic cell, major cell subset counts, and antibody-dependent cell-mediated cytotoxicity (ADCC) against a Her2neu(+) tumor cell line, as well as selected plasma inflammatory cytokine, chemokine and growth factor levels. Results: Our analysis comprised only the first 3 months of treatment in the initial 25 patients. Relative to pretreatment baseline values, white blood cell, neutrophil, MO, and eosinophil counts increased (P = .001 for each); the proportion of platelets increased 9 days after the second (P = .002) and third (P = .04) carboplatin treatments; and the number of cells in the activated MO subsets CD14+HLA-DR+, CD14+CD64+, and CD14(+)CXCR3(+) increased (P <= .04 for each); plasma levels of the proangiogenic interleukins 1 alpha, 6, and 8 were lower (P <= .03 for each); M-CSF, a product of activated MO/MA, was increased on day 9 (P = .007); and GM-CSF was increased in plasma after GM-CSF administration (P <= .04). Quality of life measurements were reduced during the GM-CSF/IFN-gamma 1b cycle while recovering at pre-chemotherapy baseline for FACT-G scores only. Conclusion: A novel regimen of GM-CSF plus IFN-gamma 1b administered to 25 EOC patients receiving carboplatin increased myeloid cells, platelets and total activated MO populations during the initial 3 months; however, ADCC responses were not consistently enhanced during this period.