Background: Malignant peripheral nerve sheath tumors (MPNSTs) are rare cancers associated with neurofibromatosis type 1 (NF1). The development of MPNST is the foremost complication contributing to early mortality and overall decrease in life expectancy in NF1 patients. Poor survival is associated with MPNSTs, particularly with recurrent tumors, tumors located in the head, neck or trunk, high grade histology, and positive surgical margins. When compared with sporadic tumors, MPNSTs associated with NF1 have a far worse prognosis. The 5-year survival rate after diagnosis is 21% for NF1 patients with MPNST, compared to 42% for sporadic cases of MPNST. MPNSTs lack effective treatment options, as they are often resistant to chemotherapies and have high rates of recurrence. With few treatment inroads and historically poor outcomes, new therapies are urgently needed for this life-limiting complication of NF1.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 human thyroidal sodium-iodide symporter (NIS). The virus is selectively oncolytic, targeting and destroying tumor cells through the type I membrane protein CD46, a membrane regulator of complement activation that is known to be overexpressed on many human malignant cells. CD46 is the cellular receptor for MV-NIS, mediating both virus entry and subsequent cell killing through cell-cell fusion. The cytopathic effect of MV-NIS increases exponentially as the density of CD46 receptors on target cells increases and is therefore dramatic at high CD46 receptor densities (tumor) but minimal at low densities (normal tissues). NIS expression in MV-NIS infected cells permits noninvasive monitoring of virus spread by serial gamma camera imaging of radioiodine or Tc-99m pertechnetate uptake. In addition, the anti-neoplastic activity of the virus can be amplified by administering I-131, a potently ionizing beta emitting isotope of radioiodine.Objective/Hypothesis: Our preliminary data confirm that MPNST cells are highly susceptible to MV-NIS. Our overall hypothesis is that MV-NIS administered intratumorally to patients with locally advanced/recurrent MPNST will selectively propagate in the tumor, leading to tumor cell eradication and reduction of tumor burden. This hypothesis will be tested by serial gamma camera or SPECT-CT imaging of Tc-99m pertechnetate uptake after MV-NIS therapy to monitor the changing number and location of virus-infected cells. Intratumoral injection of MV-NIS into MPNSTs is feasible, and intratumoral spread of the virus will be monitored noninvasively by nuclear imaging. This clinical trial is guided by the following specific aims:Specific Aim 1: To determine the maximum tolerated dose by this route.Specific Aim 2: To perform pharmacokinetic studies to determine the location of virus-infected cells, the time course of viral gene expression, the evolution of the anti-measles antibody response, and its impact on the virus.Specific Aim 3: To obtain preliminary evidence for anti-tumor activity in human subjects.Study Design: We propose to conduct a Phase I clinical trial to evaluate the safety of MV-NIS administered intratumorally to patients with locally advanced, recurrent, or metastatic MPNST. The treatment protocol includes intratumoral administration of MV-NIS under ultrasound or CT guidance (by an interventional radiologist), in vivo monitoring of distribution and kinetics of virus using SPEC/CT or planar gamma camera imaging after TC-99m administration, and assessing changes in tumor size by using WHO (World Health Organization) criteria. Our correlate studies will explore the time course of viral gene expression, virus elimination, and humoral and cellular immune response to the injected virus.Clinical Impact: Development of an efficient and well-tolerated therapy for MPNSTs may provide a therapeutic option for patients with non-operable MPNST, and as such, prolong survival and increase the overall life expectancy for patients with NF1. More broadly, if this treatment proves to be efficient in NF1-derived MPNSTs, it would open the possibility for oncolytic viral therapy to be used as a platform for the development of therapy for other NF1-related tumors, including plexiform neurofibromas.
|Effective start/end date||9/15/15 → 9/14/19|
- Congressionally Directed Medical Research Programs: $1,338,626.00