A phase I study of anti-GD3 ganglioside monoclonal antibody R24 and recombinant human macrophage-colony stimulating factor in patients with metastatic melanoma

Abstract

Background. Macrophages activated by macrophage‐colony stimulating factor (M‐CSF) are potent immune effector cells and can mediate both in vitro cytotoxicity and antitumor effects in vivo. A Phase I trial combining M‐CSF with R24, a mouse monoclonal antibody against GD3 ganglioside that has been shown to localize to melanoma tumors, induce inflammation at tumor sites, and result in major tumor responses in some patients with melanoma was performed. Methods. Nineteen patients with metastatic melanoma received a 14‐day continuous intravenous infusion of 80 80μg/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 μg/m2/day. Results. All patients developed pruritus and urticaria; 13 patients developed transient thrombocytopenia less than 100,000/mm3. 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 represent a subpopulation of monocytes active in mediating antibody‐directed cellular cytotoxicity. Other biologic effects of treatment included marked but transient decreases in total cholesterol, low density lipoprotein, and high density lipoprotein. Three patients experienced tumor regression in breast, liver, and lymph node metastases and received a second course of therapy. Six of the 19 patients, one of whom received no 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 remains alive at 37+ months. Conclusions. Combination therapy with R24 and M‐CSF resulted in both clinical and biologic effects that warrant further investigation of this combination.

Oncotargets GD2 and GD3 are highly expressed in sarcomas of children, adolescents, and young adults

“…Seminal trials in melanoma using R24 (GD3‐specific IgG3 antibody) demonstrated a major tumor regression in patients with advanced disease . Most common toxicities of GD3 antibody include pruritus and urticaria . The high prevalence of GD3 expression in sarcomas and DSRCT shown in this study should provide a rationale for future antibody strategies directed at these tumors.…”

Bioengineering of Surface GD3 Ganglioside for Immunotargeting Human Melanoma Cells

“…A murine mAb (R24) recognizing GD3 has been tested in patients in various clinical trials. Regression of melanoma metastasis after treatment has been documented repeatedly (22)(23)(24)(25)(26). More recently, a chimeric antibody KM871 showed its efficacy in the treatment of melanomas in a nude mice model by slowing the tumor growth (27).…”

Recombinant human macrophage colony‐stimulating factor‐induced thrombocytopenia in dogs

“…Thrombocytopenia has been associated with the administration of a number of cytokines, including GM-CSF (Nash et al, 1995), M-CSF (Koike et al, 1986;Sanda et al, 1992;Minasian et al, 1995), G-CSF (Lindemann et al, 1989), IL-2 (Paciucci et al, 1990), stem cell factor (SCF) (Schuening et al, 1993) and Flt3 ligand (unpublished observations). There may be a common mechanism responsible for cytokine-related decreases in platelet counts.…”