title: Clinical and immunological effects of granulocyte-macrophage colony-stimulating factor coadministered with interleukin 2: a phase IB study.
abstract: Interleukin 2 (IL-2) and granulocytes-macrophage colony-stimulating factor (GM-CSF) are activators of the lymphocyte and granulocyte/macrophage series, respectively. We conducted a phase IB trial to identify the maximally tolerated dose and to assess immunological effects of the combination. Thirty-four patients with incurable cancers received 2.5, 5, or 10 microgram/kg GM-CSF s.c. either before or concurrently with 1.5 or 3.0 million units/m2/day IL-2. The most common laboratory and clinical side effects included an elevation of the total WBC or eosinophil count due to GM-CSF, and constitutional symptoms due to IL-2. Grade 3 or 4 toxicities included hypotension, thrombocytopenia, elevations in aspartate aminotransferase or bilirubin, renal toxicity, gastrointestinal hemorrhage, arrhythmia, and constitutional symptoms. Two patients receiving 5.0 microgram/kg GM-CSF plus concurrent 3.0 million units IL-2 experienced dose-limiting grade 3 or 4 neurological toxicity, which reversed almost completely. An increase in the serum-soluble IL-2 alpha chain receptor was observed with administration of GM-CSF, IL-2, or the combination. IL-2 therapy enhanced lymphokine-activated killer activity, antibody-dependent cellular cytotoxicity, and lymphocyte activation, with increased CD16 and CD56 expression. GM-CSF increased expression of human leukocyte antigen DR on peripheral blood monocytes and decreased surface expression of CD16 on circulating monocytes and polymorphonuclear cells. Lymphokine-activated killer activity and CD16 expression on monocytes and lymphocytes and CD56 expression on lymphocytes were significantly lower in patients receiving GM-CSF simultaneously with IL-2 than in patients receiving the sequential treatment. Antitumor activity was observed in the lungs of four of eight renal cell carcinoma patients with pulmonary metastases treated with concurrent GM-CSF and IL-2. Although no or minimal shrinkage was observed in the patients' large primary tumors, these results warrant further study. The recommended initial Phase II dose and schedule is 1.25 microgram/kg/day GM-CSF, given concurrently with 1.5 million Roche units/m2/day (4.5 x 10(6) international units/m2/day) IL-2, with subsequent escalation of GM-CSF to 2.5 microgram/kg/day after careful observation for toxicities.
authors.affiliation: University of Wisconsin Comprehensive Cancer Center, Departments of Human Oncology and Medicine, Madison, Wisconsin 53792, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Schiller
authors.forename: J A
authors.initials: JA
authors.lastname: Hank
authors.forename: M
authors.initials: M
authors.lastname: Khorsand
authors.forename: B
authors.initials: B
authors.lastname: Storer
authors.forename: A
authors.initials: A
authors.lastname: Borchert
authors.forename: K
authors.initials: K
authors.lastname: Huseby-Moore
authors.forename: D
authors.initials: D
authors.lastname: Burns
authors.forename: O
authors.initials: O
authors.lastname: Wesly
authors.forename: M R
authors.initials: MR
authors.lastname: Albertini
authors.forename: G
authors.initials: G
authors.lastname: Wilding
authors.forename: P M
authors.initials: PM
authors.lastname: Sondel
mesh_terms: D000328:Adult; D000368:Aged; D000920:Antibody-Dependent Cell Cytotoxicity; D019002:CD56 Antigen / Q000032:analysis; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage* / Q000009:adverse effects; D006684:HLA-DR Antigens / Q000032:analysis; D006801:Humans; D007376:Interleukin-2 / Q000008:administration & dosage* / Q000009:adverse effects; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D017452:Receptors, IgG / Q000032:analysis; D015375:Receptors, Interleukin-2 / Q000032:analysis
chemical_list: D019002:CD56 Antigen; D006684:HLA-DR Antigens; D007376:Interleukin-2; D017452:Receptors, IgG; D015375:Receptors, Interleukin-2; D016178:Granulocyte-Macrophage Colony-Stimulating Factor