Development of ONCR-NEP, a lipid nanoparticle delivered oncolytic virus capable of robust in situ amplification resulting in tumor lysis and regression

Oncolytic viruses (OV) have shown clinical efficacy for treatment of malignancies when administered intratumorally. Attempts to use OV for systemic treatment of cancer have shown very limited success due to the presence of neutralizing antibodies. Development of an intravenously delivered oncolytic viral therapy that maintains its potency and effectiveness in the presence of neutralizing antibodies is greatly needed for patients with visceral lesions that are metastatic and difficult to inject. Therefore, the OV field is moving toward the design of vector platforms that can be used for systemic therapy to take full advantage of the oncolytic activity and the induction of anti-tumor immunity. Oncorus is developing a new strategy for systemic delivery of OV genomes by using tumor targeted nanoparticles, designed to be immunologically inert systemically, but can initiate a local robust intratumoral oncolytic virus infection. The Nanoparticle Encapsulated Polynucleotide (NEP) platform is designed for systemic delivery of replication competent OV genomes encoded by a plasmid DNA loaded into tumor-homing nanoparticles. To initiate viral replication intratumorally from a plasmid DNA we engineered a mammalian mRNA cassette that codes for an infectious +sense picornaviral RNA. This RNA is liberated from the larger capped and polyadenylated mammalian transcript by combination of ribozymes and siRNA cleavage, enabling rapid expression of viral proteins and viral replication. We selected Seneca Valley Virus (SVV) as our first candidate virus for the NEP platform. SVV is a potent oncolytic virus in neuroendocrine tumors previously evaluated in clinical trial after IV administration and well tolerated in the patients. The robust initiation of SVV replication from the pDNA expression construct results in cellular lysis in permissive cells when transfected in vitro. In vivo, intratumoral injection of a lipid based formulated SVV plasmid resulted in robust viral replication and dramatic tumor growth inhibition in multiple tumor models. This viral construct has also been modified to express immunomodulatory payloads to enhance the adaptive immune response by recruitment of immune effector cells. Finally, we have enabled miRNA attenuation of his construct to add a genetic tissue selectivity switch for safety, and we have shown that both miR-1 and miR-122 effectively and specifically attenuate viral replication. To enable ONCR-NEP therapy for intravenously administration, we have begun developing a lipid nanoparticle formulation with an active tumor targeting moiety. We have obtained lipid nanoparticle formulations with favorable physical and functional characteristics that are effective both in vitro and in vivo. We show here for the first time the development of a synthetic virus, a breakthrough therapeutic technology that is highly effective in vivo. Citation Format: Edward M. Kennedy, Jennifer S. Lee, Judy Jacques, Terry Farkaly, Prajna Behara, Peter Grzesik, Brian B. Haines, Agnieszka Denslow, Jacqueline Gursha, Lingxin Kong, Mitchell Finer, Christophe Queva, Lorena Lerner. Development of ONCR-NEP, a lipid nanoparticle delivered oncolytic virus capable of robust in situ amplification resulting in tumor lysis and regression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4773.