Abstract 5334: Oncolytic Newcastle disease virus: armed but not dangerous

Abstract

Abstract Oncolytic viruses are live, replication-competent viruses that infect and/or replicate selectively in tumour cells leading to the destruction of the infected cell. Cell lysis occurs as a natural consequence of the viral life cycle and released virions can infect and kill neighbouring tumour cells leading to an amplified therapeutic effect. Oncolysis has the added benefit of releasing multiple tumour antigens that may further induce an immune-mediated therapeutic response. Newcastle Disease Virus (NDV) is an avian paramyxovirus, which has proven safety and demonstrated efficacy against a variety of preclinical cancer models and in PhI clinical studies as an oncolytic agent, oncolysate or whole cell vaccine. Using reverse genetics, we have generated a recombinant strain of NDV that overcomes environmental and regulatory concerns uncoupling oncolytic potency and avian pathogenicity. Furthermore we have enhanced the immune modulatory properties of NDV by engineering the virus to express granulocyte/macrophage colony-stimulating factor (GM-CSF). We have evaluated the biological characteristics of recNDVGM-CSF in vivo and in vitro. RecNDVGM-CSF selectively replicates in and kills a wide variety of human and mouse tumour cell lines. Additionally NDV infection of cancer cells results in the increased production and secretion of pro-inflammatory cytokines and chemokines which are able to recruit mediators of both the innate and adaptive immune responses. NDV is a potent activator of the type I interferon response and is also able to directly activate many immune cell types. In vivo, using a range of syngeneic and xenograft models we have demonstrated that NDV treatment has profound anti-tumour activity. In a HT1080 fibrosarcoma xenograft model a single administration (intra-tumoural or systemic) was able to cure 80% of tumour bearing mice. In syngeneic mouse tumour models, NDV treatment causes profound changes in the immune suppressive microenvironment and can result in long-lasting anti-tumour immune responses. The inherent properties of NDV (self-propagation, tumour-selective replication, and immunostimulatory properties) coupled with the ability to genetically engineer NDV to express therapeutic transgenes may provide a multi-modal attack on the tumour, delivering greater benefit to patients. Citation Format: Danielle K. Carroll, James Harper, Shannon Burke, Jon Travers, Ruth Franks, Christel Navarro, Xing Cheng, Robert W. Wilkinson, Hong Jin. Oncolytic Newcastle disease virus: armed but not dangerous. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5334. doi:10.1158/1538-7445.AM2015-5334