Efficacy of intrathecal immunotoxin therapy in an animal model of leptomeningeal neoplasia

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Abstract
Immunotoxins comprise a new class of cell-type specific cytotoxic reagents which consist of a monoclonal antibody linked to a protein toxin. This report examines the efficacy of intrathecal immunotoxin therapy for the treatment of tumors of the cerebrospinal fluid compartment. A syngeneic animal model of leptomeningeal neoplasia was developed in which percutaneous inoculation of L2C tumor cells into the cisterna magna of Strain 2 guinea pigs produced disseminated leptomeningeal and intraventricular leukemia and death. Percutaneous intracisternal injection of 2 micrograms of an anti-idiotype monoclonal antibody (M6)-intact ricin immunotoxin 24 hours following intracisternal inoculation of 10(5) L2C cells (10,000 times the lethal dose) produced prolonged survival (p less than 0.005) of tumor-bearing animals. The immunotoxin therapy caused no detectable toxicity. Intracisternal injection of either M6 monoclonal antibody alone or a nonspecific control immunotoxin had no therapeutic effect. The observed extension of survival times in immunotoxin-treated animals corresponds to a median 2- to 3-log (99% to 99.9%) and, in some animals, possibly a 5-log (99.999%) or greater kill of tumor cells. These results support a possible role for immunotoxins in the clinical treatment of central nervous system neoplastic disease involving compartments (intrathecal, intraventricular, or cystic tumor).