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 
The strategy pursued in our laboratories is to modify HSV-1 tropism, and efficiently retarget the virus to cancer-associated cell-surface molecules, such as the human epithelial growth factor receptor 2 (HER-2), a member of the tyrosine kinase receptors 
. The clinical impact of the HER-2 oncogene stems from the fact that it is overexpressed in human breast and ovary carcinomas (>200,000 new cancer cases each year in the U.S.), and correlates with worsened prognosis. Because of these properties, HER-2 is currently the target of antibody-based (trastuzumab) therapies, or small molecule tyrosine kinase inhibitors.
We took advantage of the fact that HSV encodes a multipartite fusion/entry apparatus made of four essential glycoproteins, and that one of these, gD, is the major determinant of the viral tropism 
. Replacement of the Ig-folded gD core with a single chain antibody to HER-2 subverts the viral tropism, and enables HSV to selectively infect HER-2+ cancer cells and spare the usual targets. By this strategy, the killing capacity of wt-virus is fully preserved, and the high safety profile has not been achieved at the expenses of replication, as was the case in earlier oncolytic-HSV (o-HSV) which were deleted of virulence genes, and overall attenuated in replication capacity 
. Previous studies from our laboratories showed that the HER-2-retargeted R-LM249 exerts antitumor activity when administered intratumorally to nude mice bearing HER-2-hyperexpressing human tumors 
. A single injection dramatically impaired tumor growth. Repeated injections of R-LM249 doses higher than 106
pfu left 60% of mice tumor-free, and dramatically reduced the tumor size in the remaining 40%. Recently, a HSV retargeted to HER-2 showed efficient antitumor activity in an intracranial model of high-grade glioma in immunosuppressed and immunocompetent mice 
. Overall, these findings demonstrated that R-LM249 is effective in killing HER-2+ tumors in vivo, when administered locally 
The major clinical problem of HER-2+ neoplasms is disseminated disease, not the primary tumors which are usually removed surgically, coupled to the development of cells resistant to the biological inhibitors. Ovarian cancer disseminates within the peritoneal cavity, thus hampering surgical resection, and frequently produces voluminous peritoneal ascites 
. Breast cancer disseminates systemically, most frequently to lungs, peritoneal organs, bones, brain in addition to peritoneal cavity 
. Here we performed the preclinical evaluation of i.p. administered R-LM249 against peritoneal metastases of human ovarian and breast cancers in murine hosts. We show that the i.p.-administered HER-2-redirected HSV effectively inhibits peritoneal dissemination of HER-2+ ovarian and mammary carcinomas.