Targeted Alpha Therapy with (227) Th-trastuzumab of Intraperitoneal Ovarian Cancer in Nude Mice

The aim of the current study was to investigate the therapeutic effect of (227) Th-radioimmunotherapy on intraperitoneally growing human bioluminescent HER2 positive ovarian cancer cells. Methods: In vitro toxicity of Th-227-trastuzumab in bioluminescent SKOV3-luc-D3 ovarian cancer cells was assessed in a growth assay. The biodistribution of intraperitoneally administrated Th-227-trastuzumab in athymic nude mice without tumor cells was determined. For in vivo therapy, seventy female athymic nude mice were intraperitoneally inoculated with tumor cells 17 days prior to injection of single Th-227-trastuzumab doses of 1000 kBq/kg, 600 kBq/kg or 400 kBq/kg, or three injections with 400 kBq/kg Th-227-trastuzumab separated by 4 weeks. Two control groups were given either 20 mu g unlabeled trastuzumab or 0.9 % NaCl. In vivo bioluminescence imaging was performed weekly before and after onset of therapy. Tumor growth, survival and toxicity were compared. Results: There was a statistically significant therapeutic effect of the Th-227-trastuzumab treatment both with respect to survival and tumor growth. The maximum tolerated dosage was 600 kBq/kg Th-227-trastuzumab. In the in vitro study, two hours incubation with 20 kBq/ml of Th-227-trastuzumab, followed by washing, and subsequent culture of the cells resulted in an average absorbed radiation dose of 6 Gy after 11 days and complete growth inhibition. Conclusion: Targeted alpha therapy with Th-227-trastuzumab of human SKOV3-luc-D3 cells growing intraperitoneally in nude mice was clearly superior to unlabeled trastuzumab therapy. The results warrant further studies of (227) Th-radioimmunotherapy used as adjuvant treatment and for metastatic cancer.