Skin cancers are the most common form of cancer in the United States, with roughly about a million new cases each year. Melanoma is an aggressive skin cancer, and approximately 76,100 patients have been diagnosed in 2014 with melanoma in the United States, accounting for an estimated 9,710 deaths. Ultraviolet radiation from the sun is the major risk factor for melanoma and hence individuals with high sun exposure and especially with light skin tones possess a higher risk of melanoma. Despite considerable progress made in the management of advanced melanoma over the past two decades, improvement in overall survival has been elusive, with brain metastases contributing to half of all melanoma-related deaths. Metastatic-melanoma tumors in the brain have multiple tumor deposits at the time of diagnosis making surgery an inadequate therapeutic option. In addition, conventional systematic therapies to treat melanoma brain metastasis are ineffective mainly due to poor delivery of available drugs to the tumor deposits in the brain. Therefore, new therapies are urgently needed for patients with melanoma brain metastasis.

In the ongoing search for therapeutics that are capable of eliminating metastatic tumor deposits, oncolytic viruses have shown great potential in preclinical studies. Among therapeutic viruses, oncolytic Herpes Simplex Virus (oHSV) is one of the most promising candidates for therapy of tumors in the brain as it is an inherently neurotropic virus. oHSV has shown promising efficacy in treating various types of cancers, especially advanced melanomas in a number of animal studies. This has led to the use of oHSV in clinical trials in melanoma patients and there are three ongoing Phase II/III clinic trials in melanoma patients. Although these studies are promising for primary melanomas, there are currently no oHSV-based therapeutics/strategies focused on melanoma brain metastasis, which is the major cause for melanoma-related mortality. The major limitations to developing oHSV-based therapies for melanoma brain metastasis are the lack of animal models that authentically reproduces tumor growth and metastatic progression seen in melanoma patients and the inability to deliver oHSV to the tumor deposits in the brain.

In this proposal, two underlying principles will be employed to develop therapies that will directly influence the future of metastatic melanoma tumors in the brain: use of tumor selective and potent variant of oHSV (oHSV-TRAIL) that will be loaded into MSC to selectively target different melanoma tumor lines and testing the therapeutic efficacy of MSC loaded oHSV-TRAIL in our recently developed melanoma to brain metastasis model that recapitulates the clinical scenario of metastatic tumor growth. The specific aims of the proposed study are to (1) assess the mechanism-based response of melanoma lines to MSCoHSV-TRAIL in vitro and ultimately (2) evaluate the fate and therapeutic efficacy of MSC-oHSV-TRAIL in mouse model of melanoma brain metastasis. Once validated, these studies can be easily translated into clinics using patients own MSC or reprogrammed cells loaded with oHSV-TRAIL. In the next 3-5 years, we envision a therapeutic modality in which at the time of metastatic tumor detection in the brain, oHSV-TRAIL loaded therapeutic stem cells will be systemically injected into patients to target the metastatic tumor deposits. This will have a major impact in saving the lives of many metastatic melanoma cancer patients, particularly military personnel who are at a higher risk of developing such cancers.