Treatment of HER2-positive breast carcinomatous meningitis with intrathecal administration of α-particle-emitting 211At-labeled trastuzumab

Introduction: Carcinomatous meningitis (CM) is a devastating disease characterized by the dissemination of malignant tumor cells into the subarachnoid space along the brain and spine. Systemic treatment with monoclonal antibody (mAb) trastuzumab can be effective against HER2-positive systemic breast carcinoma but, like other therapies, is ineffective against CM. The goal of this study was to evaluate the therapeutic effect of alpha-particle emitting At-211-labeled trastuzumab following intrathecal administration in a rat model of breast carcinoma CM. Methods: Athymic rats were injected intrathecally with MCF-7/HER2-18 breast carcinoma cells through a surgically implanted indwelling intrathecal catheter. In Experiment 1, animals received 33 or 66 mu Ci At-211-labeled trastuzumab, cold trastuzumab or saline. In Experiment 2, animals were inoculated with a lower tumor burden and received 46 or 92 mu Ci At-211-labeled trastuzumab or saline. In Experiment 3, animals received 28 mu Ci At-211-labeled trastuzumal), 30 mu Ci At-211-labeled TPS3.2 control mAb or saline. Histopathological analysis of the neuroaxis was performed at the end of the study. Results: In Experiment 1, median survival increased from 21 days for the saline and cold trastuzumab groups to 45 and 48 days for 33 and 66 mu Ci At-211-labeled trastuzumab, respectively. In Experiment 2, median survival increased from 23 days for saline controls to 68 and 92 days for 46 and 92 mu Ci At-211-labeled trastuzumab, respectively. In Experiment 3, median survival increased from 20 days to 29 and 36 days for animals treated with At-211-labeled TPS3.2 and At-211-labeled trastuzumab, respectively. Long-term survivors were observed exclusively in the At-211-trastuzumab-treated groups. Conclusion: Intrathecal At-211-labeled trastuzumab shows promise as a treatment for patients with HER2-positive breast CM. (C) 2009 Elsevier Inc. All rights reserved.