Date Published: January 31, 2013
Publisher: Public Library of Science
Author(s): Patrizia Nanni, Valentina Gatta, Laura Menotti, Carla De Giovanni, Marianna Ianzano, Arianna Palladini, Valentina Grosso, Massimiliano Dall’Ora, Stefania Croci, Giordano Nicoletti, Lorena Landuzzi, Manuela Iezzi, Gabriella Campadelli-Fiume, Pier-Luigi Lollini, David M. Knipe.
Oncolytic viruses aim to specifically kill tumor cells. A major challenge is the effective targeting of disseminated tumors in vivo. We retargeted herpes simplex virus (HSV) tropism to HER-2 oncoprotein p185, overexpressed in ovary and breast cancers. The HER-2-retargeted R-LM249 exclusively infects and kills tumor cells expressing high levels of human HER-2. Here, we assessed the efficacy of systemically i.p. delivered R-LM249 against disseminated tumors in mouse models that recapitulate tumor spread to the peritoneum in women. The human ovarian carcinoma SK-OV-3 cells implanted intraperitoneally (i.p.) in immunodeficient Rag2−/−;Il2rg−/− mice gave rise to a progressive peritoneal carcinomatosis which mimics the fatal condition in advanced human patients. I.p. administration of R-LM249 strongly inhibited carcinomatosis, resulting in 60% of mice free from peritoneal diffusion, and 95% reduction in the total weight of neoplastic nodules. Intraperitoneal metastases are a common outcome in breast cancer: i.p. administration of R-LM249 strongly inhibited the growth of ovarian metastases of HER-2+ MDA-MB-453 breast cells. Brain metastases were also reduced. Cumulatively, upon i.p. administration the HER-2-redirected oncolytic HSV effectively reduced the growth of ovarian and breast carcinoma disseminated to the peritoneal cavity.
The past decades have witnessed remarkable progresses in the ability to treat numerous cancers by means of surgery, chemio- and radiotherapy, or combinations thereof. Nonetheless, there remains a tremendous burden of tumors not sensitive or accessible to standard treatments. Oncolytic virotherapy exploits the intrinsic ability of viruses to kill the target cell and simultaneously to spread to other target cells. A key requirement is that the virus specifically targets cancer cells . Herpes simplex virus- 1 (HSV-1) is being actively investigated in preclinical and phase 1–3 clinical studies as it lends itself to numerous genetic modifications that make it cancer-specific , .
Tumor dissemination is the main cause of cancer-related death. A major challenge in oncolytic virotherapy is whether viruses can reach metastatic tumors upon systemic (e.g. intravenous or intraperitoneal) administration. To address this issue, not previously investigated for any retargeted HSVs, we employed mouse models that mirror the intraperitoneal dissemination of the two main HER-2+ cancers, ovarian and breast. This represents an aggressive, advanced form of cancer, associated with dismal prognosis. The HER-2-redirected HSV R-LM249 was administered i.p., to ensure that it readily reached the intraperitoneal metastatic masses. R-LM249 strongly inhibited the peritoneal growth of human HER-2+ trastuzumab-resistant ovarian and breast carcinomas, and its metastatic growth in the brain, but not in the lungs.