Treatment of neoplastic meningeal xenografts by intraventricular administration of an antiganglioside monoclonal antibody, 3F8

Leptomeningeal (LM) neoplastic metastases are painful, debilitating and ine vitably lethal. Intrathecal (IT) anti-tumor antibodies may have therapeutic potential. We evaluated 3F8, an anti-GD(2) murine IgG(3) monoclonal antibo dy (MAb) in the treatment of human melanoma (SKMEL-1) and neuroblastoma (NM B7) xenografts in athymic rats. Both tumors were lysed efficiently in vitro by 3F8 in the presence of rat neutrophils or rat complement. Antibody-depe ndent cellular cytotoxicity (ADCC) was not augmented by recombinant human G M-CSF (rhGM-CSF), rhG-CSF, recombinant rat MIP-2 (rrMIP-2) or lipopolysacch aride (LPS), in vivo, continuous intraventricular administration of 3F8 and LPS prevented tumor engraftment, retarded tumor growth and eradicated 3-da y-old established xenografts whereas 3F8 alone, LPS alone or F(ab)'(2) plus LPS had no or only marginal effects. Tumor establishment in brain was comp letely prevented in 36% of animals implanted with SKMEL-1 and 65% of animal s implanted with NMB7, Twenty percent of established xenografts around the brain were eradicated but all animals had persistent tumor in the lumbosacr al meninges despite treat ment. Continuous intraventricular infusion of LPS produced a variable polymorphonuclear (PMN) pleocytosis that was dose-depe ndent. Continuous intraventricular infusion of 3F8 produced immunohistochem ically detectable attachment to 86% of persistent brain deposits of tumor b ut < 1% of spinal lumbosacral deposits;We conclude that regional therapy wi th anti-G(D2) MAb could target neutrophils to inhibit LM tumor growth. Howe ver, optimal activation and mobilization of neutrophils into the cerebrospi nal fluid (CSF) and improved penetration of MAb to tumor sites remain criti cal variables. (C) 1999 Wiley-Liss, Inc.