Reston, VA-A new 225Ac-DOTA-based pre-targeted radioimmunotherapy (PRIT) system has been shown to cure a highly lethal form of advanced intraperitoneal ovarian cancer in a preclinical setting with minimal side effects. Targeting the HER2 protein, which is commonly expressed in ovarian cancer, the therapy (anti-HER2 225Ac-PRIT) is a potential treatment for the otherwise incurable disease. This research was published in the September issue of The Journal of Nuclear Medicine.
Epithelial ovarian cancer is the most lethal ovarian cancer and frequently presents as advanced-stage disease, such as peritoneal carcinomatosis, where disease has spread throughout the peritoneal cavity. Advanced-stage disease is associated with a poor prognosis and a five-year overall survival ranging from 18 to 46 percent. Most patients die because of extensive peritoneal disease burden and malignant bowel obstruction.
"Due to the explosion of immune and targeted therapies in the past few decades-particularly those targeting HER2-there is increasing interest in the potential role of alternative, more innovative therapies to cure epithelial ovarian cancer," said Sarah M. Cheal, PhD, of the Molecular Imaging Innovations Institute in the Department of Radiology at Weill Cornell Medical College in New York, New York. "In this study, we adapted our PRIT system to target HER2 in epithelial ovarian cancer and explored whether this could effectively treat the disease without significant toxicity."
The preclinical study included five groups of eight to 10 nude mice, each bearing peritoneal carcinomatosis tumors. Two groups of mice were treated with either one or two cycles of anti-HER2 225Ac-PRIT; the other groups received alternative or no treatments and were used as controls. Weekly weights and tumor progression were monitored for up to 154 days.
Tumors spread rapidly in untreated mice, leading to a median survival of approximately four months. When treated with one or two cycles of anti-HER2 225Ac-PRIT, however, median survival was not reached after 154 days. At the end of the study, 75 percent of mice in the anti-HER2 225Ac-PRIT treatment groups were confirmed to be clinically cured. All treatments were well tolerated by the mice.
"In this study we achieved high potency with anti-HER2 225Ac-PRIT while maintaining an acceptable safety profile. These findings suggest that when scaled to human patients, we can achieve curative tumor radiation-absorbed doses without major normal organ toxicity" stated Steven M. Larson, MD, of the Department of Radiology at Memorial Sloan Kettering Cancer Center in New York.
"Furthermore," stated Nai-Kong V. Cheung, MD, PhD, of the Department of Pediatrics at Memorial Sloan Kettering Cancer Center in New York, "since DOTA-based PRIT is modular it can be adapted to other cancers and next generation PRIT using SADA (Self-Assembling DisAssembling Antibody) with potential for broad applications for compartmental (e.g. peritoneal) as well as systemic theranostics in oncology."
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| Figure 5. Minimal to mild radiation nephropathy was observed in mice treated with 1 (37 kBq) or 2 (74 kBq) cycles of HER2 225Ac-PRIT. Shown is representative hematoxylin and eosin staining of kidneys from nontreated control and mouse treated with 2 cycles of HER2 225Ac-PRIT at 154 d after tumor inoculation (treatment initiated on day 15). Scale bar for top images: 500 μm. Scale bar for bottom images: 50 μm. |
The authors of "Efficacy of HER2-Targeted Intraperitoneal 225Ac α-Pretargeted Radioimmunotherapy for Small-Volume Ovarian Peritoneal Carcinomatosis" include Sebastian K. Chung, Christopher S. Chandler, Garrett M. Nash, and Andrea Cercek, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York; Daniela Burnes Vargas, Shin H. Seo, Blesida Punzalan and Mitesh Patel, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York; Sumudu Katugampola and Roger W. Howell, Division of Radiation Research, Department of Radiology and Center for Cell Signaling, New Jersey Medical School, Rutgers University, Newark, New Jersey; Darren R. Veach and Michael R. McDevitt, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York, and Department of Radiology, Weill Cornell Medicine, New York, New York; Brett A. Vaughn and Sarah M. Cheal, Department of Radiology, Weill Cornell Medicine, New York, New York, and Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York; Sara S. Rinne, Department of Radiology, Weill Cornell Medicine, New York, New York, and Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York; Hong Xu, Hong-Fen Guo, and Nai-Kong V, Cheung, Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York; Pat B. Zanzonico, Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, New York; Sébastien Monette, Laboratory of Comparative Pathology, Memorial Sloan Kettering Cancer Center, Weill Cornell Medicine, and Rockefeller University, New York, New York; Guangbin Yang and Ouathek Ouerfelli, Organic Synthesis Core Facility, Memorial Sloan Kettering Cancer Center, New York, New York; Edward K. Fung, Department of Radiology, Weill Cornell Medicine, New York, New York; and Steven M. Larson, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York, Department of Radiology, Weill Cornell Medicine, New York, New York, and Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
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