Human cytokines, tumor necrosis factor, and interferons: Gene cloning, animal studies, and clinical trials

Presented is a comprehensive program designed to isolate human cytokine genes and investigate their relative induction, and to analyze cytokine activities in cell culture, animal tumor models, and human clinical trials. Human cytokine cDNAs have been isolated from a cDNA library made from normal human peripheral blood leukocytes (PBLs) treated with Sendai virus and the relative induction of tumor necrosis factor (TNF), alpha and gamma interferons (IFN‐α, IFN‐γ), and interleukin‐1 beta IL‐1β genes has been analyzed. In the Sendai virus‐induced PBL system, IL‐1β mRNA was shown to be approximately twofold higher than TNF or IFN‐α mRNA whereas IFN‐γ mRNA was 50–100‐fold lower than TNF or IFN‐α mRNA. The cytotoxic activity of TNF was analyzed on several cell lines and IFN‐α and IFN‐γ were shown to potentiate TNF cytotoxicity about 2–200‐fold depending on cell lines. The LD₅₀ for recombinant TNF in BALB/c mice was determined to be 6 × 10⁷ U/kg and the therapeutic dose of recombinant TNF in sarcoma 180 bearing BALB/c mice was 3 × 10⁵ U/kg, indicating a wide therapeutic index. Phase I clinical trials of recombinant TNF given I.V. indicated a tolerated dose of 150,000 U/kg with biphasic half‐life (T‐1/2) of 2 and 31 min following TNF injection. Phase II trials of TNF and trials of TNF combined with IFN‐α are in progress. These studies indicate that cytokines such as TNF and IFN‐α are subject to similar induction systems, potentiate each other's activities, and can be tolerated at specific doses for potential therapeutic use.