CLINICAL AND IMMUNOLOGICAL EFFECTS OF GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR COADMINISTERED WITH INTERLEUKIN-2 - A PHASE IB STUDY

Interleukin 2 (IL-2) and granulocytes-macrophage colony-stimulating fa ctor (GM-CSF) are activators of the lymphocyte and granulocyte/macroph age series, respectively. We conducted a phase IB trial to identify th e maximally tolerated dose and to assess immunological effects of the combination, Thirty-four patients with incurable cancers received 2.5, 5, or 10 mu g/kg GM-CSF s.c. either before or concurrently with 1.5 o r 3.0 million units/m(2)/day IL-2. The most common laboratory and clin ical 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, gastrointest inal hemorrhage, arrhythmia, and constitutional symptoms. Two patients receiving 5.0 mu g/kg GM-CSF plus concurrent 3.0 million units IL-2 e xperienced dose-limiting grade 3 or 4 neurological toxicity, which rev ersed almost completely. An increase in the serum-soluble IL-2 alpha c hain receptor was observed with administration of GM-CSF, IL-2, or the combination, IL-2 therapy enhanced lymphokine-activated killer activi ty, antibody-dependent cellular cytotoxicity, and lymphocyte activatio n, with increased CD16 and CD56 expression. GM-CSF increased expressio n of human leukocyte antigen DR on peripheral blood monocytes and decr eased surface expression of CD16 on circulating monocytes and polymorp honuclear cells. Lymphokine-activated killer activity and CD16 express ion on monocytes and lymphocytes and CD56 expression on lymphocytes we re significantly lower in patients receiving GM-CSF simultaneously wit h IL-2 than in patients receiving the sequential treatment, Antitumor activity was observed in the lungs of four of eight renal cell carcino ma patients with pulmonary metastases treated with concurrent GM-CSF a nd IL-2. Although no or minimal shrinkage was observed in the patients ' large primary tumors, these results warrant further study, The recom mended initial Phase II dose and schedule is 1.25 mu g/kg/day GM-CSF, given concurrently with 1.5 million Roche units/m(2)/day (4.5 x 10(6) international units/m(2)/day) IL-2, with subsequent escalation of GM-C SF to 2.5 mu g/kg/day after careful observation for toxicities.