665. Toxicity and Bio-Distribution of a GM-CSF-Expressing, Chimeric Oncolytic Adenovirus ONCOS-102

Abstract

INTRODUCTION: ONCOS-102 is a serotype 5 adenovirus, comprising a chimeric capsid for enhanced gene delivery to cancer cells and a 24 bp deletion in Rb binding site of E1A region for cancer cell restricted replication. ONCOS-102 is armed with granulocyte-macrophage colony-stimulating factor (GM-CSF) for an enhanced immunostimulatory effect. ONCOS-102 treatment is a promising immunotherapy strategy for advanced cancer by directly recruiting antigen presenting cells (APC) at tumor site leading to an induction of adaptive tumor-specific CD8+ T cell response. It's immunological activity has already been demonstrated in Phase I clinical study. In this phase 1 study, local treatment of pleural mesothelioma with ONCOS-102 induced a systemic antitumor CD8+ T-cell response, prominent infiltration of CD8+ lymphocytes and Th1 type polarization.PURPOSE OF THE STUDY: The aim of this study was to evaluate the toxicity profile and biodistribution of ONCOS-102 after intracardial and repeated intraperitoneal or subcutaneous administration in Syrian hamsters.METHOD: This study was performed in compliance with the OECD principles of GLP. 300 Syrian hamsters were divided into nine groups, each group containing males and females in the same ratio. ONCOS-102 was administered in NaCl solution by intracardial, intraperitoneal or subcutaneous injections. The control animals were administered with NaCl solution without ONCOS-102 in the same volume and the same way. Hamsters were checked daily for mortality and clinical signs. Body weight and food consumption were recorded weekly. For bio-distribution analysis, hamsters were euthanized on days 0, 3, 29, and 183 and tissues and organs were collected for assessment of viral DNA. Gross necropsy and histological examination of tissues and organs were performed on days 29 and 190.RESULTS: Treatment with ONCOS-102 had no effects on body weight and food consumption. No treatment related premature deaths occurred. Apart from some findings that were not related to treatment, none of the hamsters showed signs of intoxication in the course of the first four weeks of the study. No considerable differences in hematology and clinical chemistry parameters were observed in any of the treatment groups when compared to control animals after 26 weeks of the study and recovery period. ONCOS-102 did not cause gross or histopathological changes in liver and kidneys of animals indicative of a toxic effect. The highest accumulation of viral DNA was seen in heart, liver, lungs, spleen, kidneys and bone marrow. An overall decrease of concentration of viral DNA was observed from Day 3 to Day 29 and Day 183. No adverse effects of repeated administration of ONCOS-102 on clinical signs, hematology and clinical chemistry parameters or histopathology were observed in the course of 6-month administration and following 3- month recovery period.CONCLUSIONS: Under the conditions of the study, administration of hamsters with ONCOS 102 was well tolerated, without significant signs indicating toxic effects