Subcutaneous recombinant gamma interferon in cancer patients: toxicity, pharmacokinetics, and immunomodulatory effects.
Recombinant gamma interferon (r gamma-IFN) was administered s.c. daily to 26 patients with advanced cancer. Patients were assigned to one of six doses: 0.5, 1, 2, 4, 6, or 8 million units (MU)/m2 per d. The major toxicities were an influenza-like syndrome and fever, seen in all patients. Dose limiting toxicity occurred in 4 of 4 patients treated at 8 MU/m2. One patient with nodular poorly differentiated lymphocytic lymphoma had a mixed response, and two patients with renal cell cancer have had stabilization of disease for greater than 10 and greater than 12 months. Pharmacokinetic analysis, by radioimmunoassay, revealed mean serum r gamma-IFN concentrations up to 17 ng/ml, with maximal serum levels noted 6 to 13 h after injection. In vivo immunomodulation was assessed by natural killer (NK) cytotoxicity, monocyte activation as determined by cell surface expression of HLA-Dr, and peripheral blood mononuclear cell phenotype analysis by flow cytometry. The mean T4/T8 ratio increased from 2.1 pretreatment to 4.1 after 24 h of treatment, but returned to baseline after 7 and 28 days of treatment. Augmentation of NK function was noted after 7 days of treatment. Monocyte cell surface expression of HLA-Dr increased after 28 days of treatment at the three lowest doses. In conclusion, daily s.c. r gamma-IFN can be easily administered on an outpatient basis with minimal local skin toxicity, results in prolonged serum levels, and is associated with immunological changes of potential antitumor significance. Further study of the in vivo immunomodulatory effects induced by r gamma-IFN is indicated to help define the optimal treatment regimen.
D000328:Adult; D000368:Aged; D003602:Cytotoxicity, Immunologic; D005260:Female; D005334:Fever / Q000139:chemically induced; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism / Q000627:therapeutic use* / Q000633:toxicity; D007694:Killer Cells, Natural / Q000276:immunology; D007970:Leukopenia / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism / Q000627:therapeutic use* / Q000633:toxicity; D013601:T-Lymphocytes / Q000276:immunology
D011994:Recombinant Proteins; D007371:Interferon-gamma