1. ¹Taussig Cancer Center, Center for Hematology and Oncology Molecular Therapeutics, Cleveland Clinic Foundation, Cleveland, Ohio, USA
2. ²James Cancer Center, The Ohio State University, Columbus, Ohio, USA
3. ³Department of Biostatistics and Epidemiology, Cleveland Clinic Foundation, Cleveland, Ohio, USA
4. ⁴Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, 44195, USA
5. ⁵Shanghai Institute of Biologic Products, Shanghai, China

Correspondence: EC Borden, (bordene@ccf.org)

Received 19 April 2006; Accepted 7 November 2006.

Abstract

Interferon-1 (IFN-1), which may have a primary role in innate immunity, differs significantly in amino-acid sequence from IFN-2, the only recombinant IFN- with substantial clinical evaluation. Patients with metastatic malignancies received daily subcutaneous doses of 1.5–270 g/m² of recombinant IFN-1b. Gene modulation, pharmacokinetics, tolerability, and disease response were determined. Significant (P<0.01) dose and gene-dependent increases of 2-10 fold occurred in IFN-stimulated genes, including four (tumor necrosis factor-related apoptosis-inducing ligand, cig 5, p56, GEM) never previously identified as increased in patients; significant increases (P<0.01) resulted at the lowest dose (1.5 g/m²; 1.5 10⁴ human antiviral units/m²). Increases (P<0.01) were sustainable for >4 weeks. Peak levels of IFN-1b were at 3 h; an increase of approximately eightfold in both C_max and AUC occurred between 15 g/m² and 270 g/m². Chronic toxicities of anorexia, weight loss, and fatigue were relatively uncommon. Eighteen patients were treated for >8 weeks; none experienced >grade 1 weight loss. Three patients at the highest dose developed grade 3 fatigue after 3 months, which required dose reduction or discontinuation. Patient acceptability of fatigue defined a dose for initiation of Phase II trials, 270 g/m². Six patients (five with renal cell carcinoma) had progression-free survival for >1 year, including two who had partial responses. IFN-1b resulted in potent stimulation of IFN-regulated genes and tumor regressions in renal cell carcinoma. Unique gene modulatory effects, when coupled with the moderate severity of side effects and a potentially central role in innate immunity, provide rationale for further clinical evaluation of IFN-1 in virus infections and cancer.