Loco-regional radioimmunotherapy of high-grade malignant gliomas using specific monoclonal antibodies labeled with 90Y: a phase I study

Abstract

A Phase I radioimmunotherapy trial was conducted in which radioconjugated monoclonal antibody (MAb) was directly infused into the tumor or postoperative tumoral bed in patients with high-grade malignant glioma. BC-4, a murine MAb that recognizes tenascin, was used in these studies. The MAb was labeled with 90Y, a pure beta emitter with maximum energy of 2.284 MeV, which can penetrate into tissue up to 0.5-0.7 cm. Stable 90Y-labeled MAb conjugates were prepared using the chelator p-isothiocyanatobenzyl derivative of diethylenetriaminepentaacetic acid (ITC-Bz-DTPA), obtaining >95% labeling efficiency and conserving the antibodies' immunoreactivity (>85%). Twenty patients, 2 with anaplastic astrocytoma and 18 with glioblastoma, were included in the study. All of the patients had been treated previously with conventional therapies (surgery, external radiotherapy, and chemotherapy) and presented with progressive disease not amenable to further treatment. A dose-escalation study was performed using doses ranging from 5-30 mCi (185-1110 MBq) of 90Y-labeled MAb BC-4. The protein dose of MAb was always 1 mg. Three patients were treated at the 5, 10, 15, and 20 mCi levels, and the 25- and 30-mCi doses were each administered to 4 patients. Systemic toxicity was completely absent in all of the patients. The maximum tolerated dose to the brain was 25 mCi (925 MBq). The average dose to the tumor was 3200 cGy/mCi. Doses to the liver, bone marrow, and kidneys were below 10 cGy/mCi in all of the cases. Biodistribution studies demonstrated that the 90Y-labeled MAb accreted exclusively in the neoplastic area without any diffusion into the normal brain or other normal organs. No clinical responses were recorded because of the very advanced stage of disease at the time of radioimmunotherapy.