Engineered Herpes Simplex Viruses for the Treatment of Malignant Peripheral Nerve Sheath Tumors

Abstract : A significant proportion of patients with neurofibromatosis type I (NF-1) will develop benign neurofibromas in their peripheral nerves that will progress to malignant tumors that are called malignant peripheral nerve sheath tumors or MPNST. These tumors grow progressively and if they cannot be completely removed surgically, they are eventually fatal. Radiation provides some benefit but is mostly ineffective and there are no proven chemotherapy type drugs or medicines that will prevent the progressive growth of these tumors. We have been working with genetically engineered human herpes simplex virus (HSV) as a means of treating nervous system tumors. We have genetically modified these viruses to make them safe and unable to grow in normal cells, but they will grow in tumor cells and will eventually cause the tumor cells to die, a process called oncolysis (tumor lysis). In addition, we have inserted several different kinds of genes in these viruses that allow them to overcome different mechanisms that tumor cells have to prevent virus growth. Our objective is to determine whether or not MPNST cells can be infected and killed by our oHSVs. We will test our panel of viruses against a panel of mouse and human MPNST cells that are maintained in tissue culture. We will examine the molecular changes in this large panel of tumor cells (tumor genotype) to determine how each virus is able to overcome each tumor s anti-virus defenses. We believe that all possible anti-virus defense mechanisms would be represented in our panel of both mouse and human MPNSTs and that we will be able to match the most effective oHSV engineered to overcome that mechanism used to block the virus.