Authors: 
P. Hallenbeck, K. Burroughs, S. Police, B. Brandenburg, D. Loesch, J. Stephenson, J. Nemunaitis, J. Poirier, C. Rudin
Category: 
Invited
Conference: 
Abstract: 

SVV-001 is a native non-pathogenic picornavirus that has exquisite tumor selectivity and therapeutic potential for cancers with neuroendocrine features, such as small cell lung cancer, carcinoid cancer, and most solid pediatric oncologies (Reddy et al., 2007; Wadhwa et al., 2007; Hales et al., 2008; Venkatraman et al., 2008). NTX-010 has many of the ideal properties of an oncolytic virus, including the lack of neutralizing activity by human blood, small size enabling efficient penetration and spread in tumors, stability, and ease of manufacturing. Preclinical testing demonstrated significant efficacy in 32 pre-established animal models including primary, orthotopic, metastatic, and syngeneic, many published to be predictive of clinical response and all utilizing intravenously administered SVV-001. SVV-001 elicits efficacy by potent cytolysis, although additional modalities are likely present in vivo. Safety of intravenously administered SVV-001was demonstrated in multiple strains of mice, pigs, and two strains of primates at doses up to 1014 vp/kg. Other then potentially macrophages no normal cell has been identified that supports replication of NTX-010. The majority of the selectivity for neuroendocrine cancers is driven by proteins involved in the binding and internalization of SVV-001. Microarray and mass spectrum analysis of surface proteins identified a profile of proteins characterizing permissive cells, including many statistically matching cancer stem cells profiles supporting additional data. One protein, integrin alpha 4, was statistically predictive of permissivity by FACS analysis. Further analysis and examination of integrin alpha 4 biology in neuroendocrine cancers supports a key role in the mechanism of tropism.

A phase I dose escalation study of intravenous SVV-001 was conducted across 5 log-increment dose cohorts from 107 vp/kg to 1011 vp/kg, in patients with NE cancers. Each study subject received a single IV infusion of SVV-001. Study endpoints included toxicity and response assessment, evaluation of viral titers and clearance in body fluids, and assessment of neutralizing antibody development.

30 patients who were progressing at the time of study entry were treated (6 small cell, 24 carcinoid-type). All small cell patients were heavily pretreated (> 3rd line) and were treated at 107 vp/kg, the lowest dose in the trial. In this cohort, median PFS was 1.2 months and median OS was 4.1 months. There is 1 long term (19 month +) survivor who had prolonged SD after progressing through prior therapies. Carcinoid patients in cohorts 1-4 have 70% SD rate and median PFS of 5.4 months (95% CI 3.6 to NE); median OS has not been reached. Cohort 5, a 12 patient expansion cohort at 1011 vp/kg restricted to carcinoid, is still being monitored and shows promising antitumor activity including improvement in carcinoid syndrome symptoms, decline in 5HIAA and other serum markers, minor responses by CT scan, and an objective PET response (>50% decrease in SUV). There were no DLTs in any cohort. Intratumoral viral replication and its persistence in tumors was demonstrated by immunohistochemistry as well as tumor associated titers. Viral clearance in body fluids was documented in all subjects and correlated temporally with development of antiviral antibodies. SVV-001 is the first non-pathogenic picornavirus not inhibited by human blood to be evaluated as an anticancer therapeutic. A single IV dose of 1011 vp/kg of SVV-001 is safe, has predictable viral kinetics, and has promising activity against NE tumors. Phase II testing of this novel agent both as a single agent and in combination with standard cytotoxic therapies is warranted.

Keywords (Optional): 
lung
cancer
oncolytic
seneca
pediatric