12/28/2023 0 Comments Flowjo acquired by bdSynthetic-SVV administration resulted in significant tumor growth inhibition (TGI) of NCI-H446 small cell lung cancer (SCLC) xenografts (Fig. Intravenous administration of Synthetic-SVV inhibits tumor growth in an SCLC cancer model 3d), indicating that systemic distribution of vRNA/LNP led to viral replication in permissive tumor cells and not in healthy tissues. At the end of the study, SVV replication was detected in tumor cells and not in liver tissue (Supplementary Fig. These modifications enhanced its efficacy compared with the SVV-001 vRNA 22 (Supplementary Fig. To enhance the potency of Synthetic-SVV, we introduced modifications in the internal ribosome entry site (IRES) 20 and a mutation in VP2 that improves viral entry 21. These termini are generated during IVT by an optimized 5′ ribozyme and runoff template produced by cleavage by a Type IIS restriction enzyme at the 3′ termini. To ensure vRNA replication is initiated after polyprotein translation, the termini of the IVT vRNA must recapitulate those of the RNA viral genome. We anticipate that this therapeutic platform will address the limitations associated with repeated IV administration and enhance the therapeutic potential of OVs. We show that Synthetic viruses are well tolerated and demonstrate tumor-selective viral production and spread in multiple tumor models, resulting in oncolysis and anti-tumor efficacy. This study reports the vRNA delivery and replication of Synthetic-SVV and Synthetic-CVA21. Their genomes are positive-sense single-stranded RNA and are sufficient to initiate the viral lifecycle after being introduced into a permissive tumor cell. As all components are synthetic we term this modality Synthetic RNA virus.įor this study, we select two picornaviruses, Seneca Valley virus (SVV) and Coxsackievirus A21 (CVA21), with well-documented oncolytic activity and clinical safety 2, 16, 17, 18, 19. Plasmid templates are engineered and optimized for in vitro transcription (IVT) of RNA virus genomes (vRNA) that, upon formulation in lipid nanoparticles (LNP), render particles with the desired biophysical properties to support repeat IV administration. Here, we describe the development of a nanoparticle-based delivery platform that enables repeat IV administration of viral immunotherapies. Advances in nanotechnology and their use to deliver nucleic acids are paving the way for new carrier systems to overcome the challenges of IV administration of OVs 14, 15. Retargeting 5, 6, cell carriers 7, 8, coating with polymers 9, 10, 11, and liposomes 12, 13 have been utilized to shield OVs from neutralizing antibodies, but none have progressed to the clinic. To maximize viral immunotherapy’s potential, strategies to avoid neutralization must be developed. However, the rapid development of neutralizing antibodies against the virus after IV administration likely limits exposure and infection of tumor cells after repeated dosing 3, 4. Intravenous (IV) delivery of OVs may enhance efficacy by exposing all tumor sites, including small metastatic lesions, to OVs. Talimogene laherparepvec (Imlygic®) 1 has demonstrated durable responses in melanoma patients when administered intratumorally, as has Coxsackievirus A21 (CAVATAK®) 2. Thus far, the therapeutic benefit of oncolytic virotherapy has been limited to intratumoral administration requiring a systemic antitumor immune response to be effective against non-injected lesions. Combining OVs with cancer immunotherapies has the potential to promote remodeling of the TME and activation of immune cells, enhancing the benefit of immune checkpoint inhibitors (ICIs) in poorly- or non-responsive tumors. Oncolytic viruses (OVs) are an attractive cancer therapeutic modality that selectively kills tumor cells and inflame the tumor microenvironment (TME). Altogether, the Synthetic RNA virus platform provides an approach that enables repeat intravenous administration of viral immunotherapy. In mouse and non-human primates, Synthetic-SVV is well tolerated reaching exposure well above the requirement for anti-tumor activity. Synthetic-SVV replication in tumors promotes immune cell infiltration, remodeling of the tumor microenvironment, and enhances the activity of anti-PD-1 checkpoint inhibitor. For two Synthetic RNA virus drug candidates, Seneca Valley virus (SVV) and Coxsackievirus A21, we demonstrate vRNA delivery and replication, virus assembly, spread and lysis of tumor cells leading to potent anti-tumor efficacy, even in the presence of OV neutralizing antibodies in the bloodstream. To circumvent this limitation and to enable repeated systemic administration of OVs, here we develop Synthetic RNA viruses consisting of a viral RNA genome (vRNA) formulated within lipid nanoparticles. The therapeutic effectiveness of oncolytic viruses (OVs) delivered intravenously is limited by the development of neutralizing antibody responses against the virus.
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