Preclinical Therapy of Disseminated HER-2+ Ovarian and Breast Carcinomas with a HER-2-Retargeted Oncolytic Herpesvirus

Abstract

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 Engineering of a Novel Ligand in gH Confers to HSV an Expanded Tropism Independent of gD Activation by Its Receptors

“…The scFv binds HER2 at high affinity (29.3 nM) [ 41 ]. In preclinical studies R-LM113 and R-LM249 exerted therapeutic effects against human breast and ovary cancers, and against a murine model of HER2 + glioblastoma [ 32 – 35 , 42 ]. Intraperitoneally-administered R-LM249 exerted therapeutic effect against metastases of ovary and breast cancers diffuse to the peritoneum, or to the brain [ 35 ].…”

HER2 Amplification Status in Feline Mammary Carcinoma: A Tissue Microarray–Fluorescence In Situ Hydridization–Based Study

“…In human beings, HER2, when overexpressed and amplified, drives the carcinogenesis, and therefore a target therapeutic approach for HER2-positive breast cancer has led to the formulation of a wide range of therapies directed against the p185 HER2 oncoprotein. 22 Herceptin, the first humanized monoclonal antibody directed against HER2, exerts its antitumor effect by blocking HER2 cleavage, stimulating a cellmediated antibody-dependent immunotoxicity and inhibiting mitogenic activity. 11,20,29 Trastuzumab in combination with pertuzumab, a monoclonal antibody that binds to an epitope Comparison between human epidermal growth factor receptor 2 (HER2) protein expression and gene amplification in feline mammary carcinomas, measured by average HER2 copy number signals/cell (>6, 4-6, <4).…”

“…It is administered prior to cancer development for the purposes of primary prevention. 16,22 Confirmatory studies with further molecular biology techniques are needed to establish a potential role of HER2 in the carcinogenesis of feline mammary tumors. Furthermore, in vitro models could properly establish a possible therapeutic predictivity in the feline species.…”

Current status of gene therapy for breast cancer: progress and challenges

“…For example, Nanni et al delivered a human epidermal growth factor receptor 2 (HER-2) targeted oncolytic virus for breast cancer and demonstrated efficacy in vivo following intraperitoneal administration. 29 Taking on board new results is also critical to success. Oncolytic HSVs are hampered by poor potency in the clinic; studies by Cody et al that highlight the value of including histone deacetylase inhibitors to improve viral transcription could have key knock-on effects to those researching advanced development of HSVs.…”