Treatment of HER2-positive breast carcinomatous meningitis with intrathecal administration of alpha-particle-emitting (211)At-labeled trastuzumab.
BACKGROUND
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 (211)At-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 muCi (211)At-labeled trastuzumab, cold trastuzumab or saline. In Experiment 2, animals were inoculated with a lower tumor burden and received 46 or 92 muCi (211)At-labeled trastuzumab or saline. In Experiment 3, animals received 28 muCi (211)At-labeled trastuzumab, 30 muCi (211)At-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 muCi (211)At-labeled trastuzumab, respectively. In Experiment 2, median survival increased from 23 days for saline controls to 68 and 92 days for 46 and 92 muCi (211)At-labeled trastuzumab, respectively. In Experiment 3, median survival increased from 20 days to 29 and 36 days for animals treated with (211)At-labeled TPS3.2 and (211)At-labeled trastuzumab, respectively. Long-term survivors were observed exclusively in the (211)At-trastuzumab-treated groups.


CONCLUSIONS
Intrathecal (211)At-labeled trastuzumab shows promise as a treatment for patients with HER2-positive breast CM.
Boskovitz
Abraham
A
Department of Pathology, Duke University Medical Center, Durham, NC 27710 USA.
McLendon
Roger E
RE
Okamura
Tatsunori
T
Sampson
John H
JH
Bigner
Darell D
DD
Zalutsky
Michael R
MR
D000512:Alpha Particles; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D001246:Astatine / Q000737:chemistry*; D001943:Breast Neoplasms / Q000150:complications / Q000378:metabolism / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007278:Injections, Spinal; D007553:Isotope Labeling; D055756:Meningeal Carcinomatosis / Q000150:complications / Q000378:metabolism / Q000532:radiotherapy*; D051379:Mice; D016499:Radioimmunotherapy; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015996:Survival Rate; D000068878:Trastuzumab; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D001246:Astatine; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab