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IFN--2b–Induced Signal Transduction and Gene Regulation in Patient Peripheral Blood Mononuclear Cells Is Not Enhanced by a Dose Increase from 5 to 10 Megaunits/m²

Authors' Affiliations: ¹ Integrated Biological Sciences Graduate Program, ² Human Cancer Genetics Program, Department of Molecular Virology, Immunology, and Medical Genetics, ³ Center for Biostatistics, and ⁴ Department of Surgery, and the Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, Columbus, Ohio

Requests for reprints: William E. Carson III, Department of Surgery, The Ohio State University, N924 Doan Hall, 410 West 10th Avenue, Columbus, OH 43210. Phone: 614-293-6306; Fax: 614-293-3465; E-mail: William.carson{at}osumc.edu.

Purpose: The precise molecular targets of IFN- therapy of melanoma are unknown but likely involve signal transducer and activator of transcription (STAT) 1 signal transduction within host immune effector cells. We hypothesized that intermediate and high doses of IFN- would be equally effective in activating patient immune cells.

Experimental Design: Eleven metastatic melanoma patients who were enrolled in a clinical trial of bevacizumab in combination with escalating doses of IFN--2b (5 megaunits/m² and then 10 megaunits/m²) were included in the study. Peripheral blood mononuclear cells (PBMC) were procured from patient blood just before therapy and again 1 h after each dose of IFN--2b and analyzed for the presence of phosphorylated STAT1, phosphorylated STAT2, and the induction of IFN-stimulated gene (ISG) transcripts.

Results: Phosphorylated STAT1 was significantly greater at the 5 megaunits/m² dose compared with the 10 megaunits/m² dose of IFN--2b (P = 0.02). In contrast, no significant difference in phosphorylated STAT2 was observed at a dose of 5 megaunits/m² compared with 10 megaunits/m² (P = 0.20). There were also no significant differences in the induction of ISGs within PBMCs between the two doses (P > 0.4 for all ISGs). Suppressor of cytokine signaling 1 and 3 (two inhibitors of IFN- signaling) transcripts were significantly higher among patient PBMCs following the 10 megaunits/m² dose of IFN- (P < 0.001).

Conclusion: These results suggest that lower doses of IFN--2b are as effective as higher doses with respect to the induction of Janus-activated kinase-STAT signal transduction and the transcription of ISGs within immune effector cells.