Background: Malignant peripheral nerve sheath tumors (MPNSTs) are cancers associated with neurofibromatosis type 1 (NF1). MPNST is the major complication of NF1, resulting in early mortality and overall decrease in life expectancy in patients with NF1. MPNSTs are associated with poor survival, particularly in recurrent tumors, tumors that have a more aggressive histology, residual tumors after surgery, and also tumors located in the head, neck, or trunk. Patients with NF1 and MPNST combined have a worse survival rate when compared with patients with these tumors who do not have NF1, with only a 21% survival rate 5 years after diagnosis. MPNSTs lack effective treatment options, as they resist chemotherapies and have high rates of disease recurrence after surgery. Therefore, new therapies for this life-limiting complication of NF1 are urgently needed.
Oncolytic viruses are promising therapeutic agents in cancers because they can selectively infect and destroy tumor cells without affecting surrounding normal tissue. MV-NIS is an attenuated measles virus (MV), engineered to express the marker, human thyroidal sodium-iodide symporter (NIS), which can be tracked by special imaging that helps to monitor the distribution and persistence of the virus in the human body. The virus selectively targets receptors that are known to be present in high density on human malignant cells but only sparsely on normal cells. This allows the virus to enter and subsequently kill tumor cells while leaving normal cells alone. MV-NIS is currently undergoing evaluation for use in a variety of cancers including leukemias, multiple myeloma, ovarian cancer, breast cancer, and brain tumors. This is its first application in NF1.
Objective/Hypothesis: Our preliminary data confirm that MPNST cells are highly susceptible to MV-NIS. We hypothesize that MV-NIS will be an effective oncolytic therapy for MPNSTs. Most people already have immunity to the measles virus, which prevents delivery of the virus to the tumor through the bloodstream. To overcome this problem, we plan to deliver the virus using intratumoral injections directly into MPNSTs. This is technically feasible and will not be significantly inhibited by anti-measles antibodies.
Trial Goals: We aim to determine (1) the maximum tolerated dose of MV-NIS delivered into a tumor by injection; (2) to evaluate intratumoral spread and elimination of the virus by non-invasive monitoring; and (3) to determine how long MV-NIS can maintain its tumor-killing properties. In addition, we will obtain preliminary evidence for anti-tumor activity in patients with MPNST.
Clinical Impact: Our results may lead to the development of a novel approach toward treatment of MPNST in patients with NF1. Development of an efficient and well-tolerated therapy may improve outcomes for many patients with MPNST. Furthermore, if the treatment proves to be effective in NF1-derived MPNSTs, it would open the possibility for oncolytic viral therapy for other NF1-related tumors.