Phase I Clinical Trial of Recombinant Oncolytic Newcastle Disease Virus for Intracranial Meningioma
King, Jamie Nicole
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Meningioma is one of the most commonly diagnosed intracranial tumors in dogs and humans. Treatment failures resulting in local recurrence and death remain common in tumors of high grade, prompting a need for additional therapeutic options that are both effective and affordable. Genetic modification of the LaSota strain of Newcastle Disease Virus (rLAS) has allowed the virus' fusion protein cleavage site to be replaced with that belonging to urokinase plasminogen activator (rLAS-uPA). This site is cleavable exclusively by the uPA receptor (uPAR), which is overexpressed in canine meningioma. The rLAS-uPA represents a targeted therapy that has the potential to be efficacious against meningioma when administered systemically. A Phase I clinical trial was designed to evaluate the safety and preliminary efficacy of rLAS-uPA administered to dogs with presumptive intracranial meningioma. The primary endpoint was to define the safety of rLAS-uPA, as determined by serial clinical and laboratory assessments during and after viral administration, using standard toxicity metrics defined by the Veterinary Cooperative Oncology Group (VCOG). Secondary end-points included anti-tumor activity quantified by magnetic resonance imaging (MRI) assessment of tumor size, and characterization of immune responses to the rLAS-uPA. Four dogs completed the trial without significant toxicity. No objective tumor responses were noted on MRI from any dog. All dogs produced antiviral antibodies and increased circulating cytokines during the course of treatment. No virus was recovered from plasma, urine, or cerebrospinal fluid. These results indicate that further investigation into the rLAS-uPA dose intensity and interval are required to further develop this therapy.
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