A PHASE-I STUDY OF ANTI-GD3 GANGLIOSIDE MONOCLONAL-ANTIBODY R24 AND RECOMBINANT HUMAN MACROPHAGE-COLONY-STIMULATING FACTOR IN PATIENTS WITHMETASTATIC MELANOMA

Background. Macrophages activated by macrophage-colony stimulating fac tor (M-CSF) are potent immune effector cells and can mediate both in v itro cytotoxicity and antitumor effects in vivo. A Phase I trial combi ning M-CSF with R24, a mouse monoclonal antibody against GD3 gangliosi de that has been shown to localize to melanoma tumors, induce inflamma tion at tumor sites, and result in major tumor responses in some patie nts with melanoma was performed. Methods. Nineteen patients with metas tatic melanoma received a 14-day continuous intravenous infusion of 80 mu g/kg/day of recombinant human M-CSF. R24 was administered daily by intravenous infusion on days 6-10 at doses of 1, 3, 10, 30, and 50 mu g/m(2)/day. Results. All patients developed pruritus and urticaria; 1 3 patients developed transient thrombocytopenia less than 100,000/mm(3 ). The maximum tolerated dose was not reached. All patients developed a monocytosis characterized by increased expression of the antigen HLA -DR and decreased expression of CD14, a phenotype reported to represen t a subpopulation of monocytes active in mediating antibody-directed c ellular cytotoxicity. Other biologic effects of treatment included mar ked but transient decreases in total cholesterol, low density lipoprot ein, and high density lipoprotein. Three patients experienced tumor re gression in breast, liver, and lymph node metastases and received a se cond course of therapy. Six of the 19 patients, one of whom received n o further therapy, survived more than 2 years and 4 of these patients remain alive 24 to 37 months after treatment. Of the six patients with liver metastases, three (50%) survived more than 2.5 years and one re mains alive at 37+ months. Conclusions. Combination therapy with R24 a nd M-CSF resulted in both clinical and biologic effects that warrant f urther investigation of this combination.