title: Phase I trial of recombinant interleukin-2 and recombinant beta-interferon in refractory neoplastic diseases.
abstract: Interleukin-2 (IL-2) and beta-interferon (beta-IFN) are cytokines with profound immunobiological effects on T-cell and natural killer (NK) cell activity; IL-2 also induces lymphokine-activated killer (LAK) cell cytotoxicity in humans. Both lymphokines induce antineoplastic activity against several refractory tumors. This Phase I study of 50 patients assessed the toxicities, maximally tolerated dose (MTD), effects on certain immune effector cells, pharmacokinetics of IL-2, and development of antibodies to the combination of subcutaneously administered IL-2 and intravenously administered beta-IFN. Fever was common. Indomethacin reduced the incidence and severity of fever and was necessary to prevent it from becoming dose-limiting. Hypotension occurred but never required pressors or produced complications. Constitutional symptoms, local skin toxicity at the site of IL-2 injection, generalized desquamation, eosinophilia, nausea, and vomiting were also observed. One patient had reversible renal dysfunction. Two patients experienced drug-related dyspnea without evidence of capillary leak syndrome; neither required intubation. Fluid retention and cardiotoxicity were not observed. The MTD was 5 x 10(6) U/m2 s.c. of IL-2 and 2 x 10(6) U/m2 i.v. of beta-IFN when given in combination. Enhancement of in vivo NK cell cytotoxicity and proliferation of T4+, T8+, and NK cells occurred. In vivo induction of LAK cell cytotoxicity was observed in three patients. Four patients developed nonneutralizing anti-IL-2 IgG antibodies, but none developed antibodies to beta-IFN. Peak IL-2 serum levels typically occurred 4 h following drug administration. Serum levels were within a factor of 3 of the peak level in the period studied, 1-6 h postinjection. No complete responses occurred. One patient with rectal cancer and one with transitional cell carcinoma each had a partial response, and 13 other patients (5 with renal cell, 4 with colorectal, and 4 other cancers) had stable disease. Induction of NK cell cytotoxicity was seen more commonly in patients with stable disease than in those with progressive disease. Combined administration of these agents is feasible with acceptable toxicity, and Phase II trials are warranted.
authors: Department of Medicine, SUNY Health Science Center, Syracuse 13210.
authors: F
authors: F
authors: Paolozzi
authors: K
authors: K
authors: Zamkoff
authors: M
authors: M
authors: Doyle
authors: M
authors: M
authors: Konrad
authors: E C
authors: EC
authors: Bradley
authors: A
authors: A
authors: Rudolph
authors: N
authors: N
authors: Newman
authors: J
authors: J
authors: Gullo
authors: A
authors: A
authors: Scalzo
authors: B
authors: B
authors: Poiesz
mesh_terms: D000328:Adult; D000368:Aged; D000888:Antibodies, Anti-Idiotypic / Q000032:analysis; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D004341:Drug Evaluation; D005260:Female; D006801:Humans; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007370:Interferon Type I / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007376:Interleukin-2 / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007694:Killer Cells, Natural / Q000276:immunology / Q000637:transplantation; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D011994:Recombinant Proteins / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D000888:Antibodies, Anti-Idiotypic; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007370:Interferon Type I; D007376:Interleukin-2; D011994:Recombinant Proteins