Treatment of neoplastic meningeal xenografts by intraventricular administration of an antiganglioside monoclonal antibody, 3F8.
Leptomeningeal (LM) neoplastic metastases are painful, debilitating and inevitably lethal. Intrathecal (IT) anti-tumor antibodies may have therapeutic potential. We evaluated 3F8, an anti-G(D2) murine IgG(3) monoclonal antibody (MAb) in the treatment of human melanoma (SKMEL-1) and neuroblastoma (NMB7) xenografts in athymic rats. Both tumors were lysed efficiently in vitro by 3F8 in the presence of rat neutrophils or rat complement. Antibody-dependent cellular cytotoxicity (ADCC) was not augmented by recombinant human GM-CSF (rhGM-CSF), rhG-CSF, recombinant rat MIP-2 (rrMIP-2) or lipopolysaccharide (LPS). In vivo, continuous intraventricular administration of 3F8 and LPS prevented tumor engraftment, retarded tumor growth and eradicated 3-day-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 completely prevented in 36% of animals implanted with SKMEL-1 and 65% of animals implanted with NMB7. Twenty percent of established xenografts around the brain were eradicated but all animals had persistent tumor in the lumbosacral meninges despite treatment. Continuous intraventricular infusion of LPS produced a variable polymorphonuclear (PMN) pleocytosis that was dose-dependent. Continuous intraventricular infusion of 3F8 produced immunohistochemically detectable attachment to 86% of persistent brain deposits of tumor but <1% of spinal lumbosacral deposits. We conclude that regional therapy with anti-G(D2) MAb could target neutrophils to inhibit LM tumor growth. However, optimal activation and mobilization of neutrophils into the cerebrospinal fluid (CSF) and improved penetration of MAb to tumor sites remain critical variables.
Departments of Pediatrics and Neurology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA. bergmai@chplink.chp.edu
I
I
Bergman
M A
MA
Barmada
G
G
Heller
J A
JA
Griffin
N K
NK
Cheung
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000134:cerebrospinal fluid; D011508:Chondroitin Sulfate Proteoglycans / Q000276:immunology*; D005260:Female; D005732:Gangliosides / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D007276:Injections, Intraventricular; D008070:Lipopolysaccharides / Q000008:administration & dosage*; D008545:Melanoma / Q000134:cerebrospinal fluid / Q000517:prevention & control* / Q000556:secondary; D008577:Meningeal Neoplasms / Q000134:cerebrospinal fluid / Q000517:prevention & control* / Q000556:secondary; D009447:Neuroblastoma / Q000134:cerebrospinal fluid / Q000517:prevention & control* / Q000556:secondary; D051381:Rats; D011923:Rats, Nude; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D011508:Chondroitin Sulfate Proteoglycans; D005732:Gangliosides; D008070:Lipopolysaccharides; C516895:PTPRZ1 protein, human; C516897:Ptprz1 protein, rat; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5