Oncolytic viruses can kill tumour cells through a dual mechanism of action; the direct lysis of cells, and the induction of an immune response. The first oncolytic virus has been approved in China, and another has been recommended for approval in the United States. This Review discusses the biology of oncolytic viruses as well as key oncolytic viruses in clinical development, and investigates the challenges associated with developing oncolytic viruses as a new therapeutic modality for cancer.

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Oncolytic viruses: a new class of immunotherapy drugs

The retinoic acid-inducible gene I product (RIG-I) has been identified as a cellular sensor of RNA virus infection resulting in beta interferon (IFN-β) induction. However, many viruses are known to encode viral products that inhibit IFN-β production. In the case of influenza A virus, the viral nonstructural protein 1 (NS1) prevents the induction of the IFN-β promoter by inhibiting the activation of transcription factors, including IRF-3, involved in IFN-β transcriptional activation. The inhibitory properties of NS1 appear to be due at least in part to its binding to double-stranded RNA (dsRNA), resulting in the sequestration of this viral mediator of RIG-I activation. However, the precise effects of NS1 on the RIG-I-mediated induction of IFN-β have not been characterized. We now report that the NS1 of influenza A virus interacts with RIG-I and inhibits the RIG-I-mediated induction of IFN-β. This inhibition was apparent even when a mutant RIG-I that is constitutively activated (in the absence of dsRNA) was used to trigger IFN-β production. Coexpression of RIG-I, its downstream signaling partner, IPS-1, and NS1 resulted in increased levels of RIG-I and NS1 within an IPS-1-rich, solubilization-resistant fraction after cell lysis. These results suggest that RIG-I, IPS-1, and NS1 become part of the same complex. Consistent with this idea, NS1 was also found to inhibit IFN-β promoter activation by IPS-1 overexpression. Our results indicate that, in addition to sequestering dsRNA, the NS1 of influenza A virus binds to RIG-I and inhibits downstream activation of IRF-3, preventing the transcriptional induction of IFN-β.

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Inhibition of Retinoic Acid-Inducible Gene I-Mediated Induction of Beta Interferon by the NS1 Protein of Influenza A Virus

Oncolytic viruses can be usefully integrated into tumour immunotherapies, as they target multiple steps within the cancer–immunity cycle. Oncolytic viruses directly lyse tumour cells, leading to the release of soluble antigens, danger signals and type I interferons, which drive antitumour immunity. In addition, some oncolytic viruses can be engineered to express therapeutic genes or can functionally alter tumour-associated endothelial cells, further enhancing T cell recruitment into immune-excluded or immune-deserted tumour microenvironments. Oncolytic viruses can also utilize established tumours as an in situ source of neoantigen vaccination through cross-presentation, resulting in regression of distant, uninfected tumours. These features make oncolytic viruses attractive agents for combination strategies to optimize cancer immunotherapy. Oncolytic viruses can target multiple steps in the cancer–immunity cycle and can be engineered to express therapeutic genes and, as a result, can be usefully integrated in combination tumour immunotherapies. Here, the authors discuss features of oncolytic viruses that make them appealing agents for combination approaches in cancer immunotherapy.

Integrating oncolytic viruses in combination cancer immunotherapy

We have generated a recombinant Newcastle disease virus (NDV) that expresses the green fluorescence protein (GFP) in infected chicken embryo fibroblasts (CEFs). This virus is interferon (IFN) sensitive, and pretreatment of cells with chicken alpha/beta IFN (IFN-α/β) completely blocks viral GFP expression. Prior transfection of plasmid DNA induces an IFN response in CEFs and blocks NDV-GFP replication. However, transfection of known inhibitors of the IFN-α/β system, including the influenza A virus NS1 protein and the Ebola virus VP35 protein, restores NDV-GFP replication. We therefore conclude that the NDV-GFP virus could be used to screen proteins expressed from plasmids for the ability to counteract the host cell IFN response. Using this system, we show that expression of the NDV V protein or the Nipah virus V, W, or C proteins rescues NDV-GFP replication in the face of the transfection-induced IFN response. The V and W proteins of Nipah virus, a highly lethal pathogen in humans, also block activation of an IFN-inducible promoter in primate cells. Interestingly, the amino-terminal region of the Nipah virus V protein, which is identical to the amino terminus of Nipah virus W, is sufficient to exert the IFN-antagonist activity. In contrast, the anti-IFN activity of the NDV V protein appears to be located in the carboxy-terminal region of the protein, a region implicated in the IFN-antagonist activity exhibited by the V proteins of mumps virus and human parainfluenza virus type 2.

Newcastle disease virus (NDV)-based assay demonstrates interferon-antagonist activity for the NDV V protein and the Nipah virus V, W, and C proteins.

H5N1 highly pathogenic avian influenza virus (HPAIV) has continued to spread and poses a significant threat to both animal and human health. Current influenza vaccine strategies have limitations that prevent their effective use for widespread inoculation of animals in the field. Vaccine strains of Newcastle disease virus (NDV), however, have been used successfully to easily vaccinate large numbers of animals. In this study, we used reverse genetics to construct a NDV that expressed an H5 subtype avian influenza virus (AIV) hemagglutinin (HA). Both a wild-type and a mutated HA open reading frame (ORF) from the HPAIV wild bird isolate, A/Bar-headed goose/Qinghai/3/2005 (H5N1), were inserted into the intergenic region between the P and M genes of the LaSota NDV vaccine strain. The recombinant viruses stably expressing the wild-type and mutant HA genes were found to be innocuous after intracerebral inoculation of 1-day-old chickens. A single dose of the recombinant viruses in chickens induced both NDV- and AIV H5-specific antibodies and completely protected chickens from challenge with a lethal dose of both velogenic NDV and homologous and heterologous H5N1 HPAIV. In addition, BALB/c mice immunized with the recombinant NDV-based vaccine produced H5 AIV-specific antibodies and were completely protected from homologous and heterologous lethal virus challenge. Our results indicate that recombinant NDV is suitable as a bivalent live attenuated vaccine against both NDV and AIV infection in poultry. The recombinant NDV vaccine may also have potential use in high-risk human individuals to control the pandemic spread of lethal avian influenza.

https://jvi.asm.org/content/jvi/81/1/150.full.pdf

Newcastle Disease Virus-Based Live Attenuated Vaccine Completely Protects Chickens and Mice from Lethal Challenge of Homologous and Heterologous H5N1 Avian Influenza Viruses

A complete cDNA clone of the Newcastle disease virus (NDV) vaccine strain Hitchner B1 was constructed, and infectious recombinant virus expressing an influenza virus hemagglutinin was generated by reverse genetics. The rescued virus induces a strong humoral antibody response against influenza virus and provides complete protection against a lethal dose of influenza virus challenge in mice, demonstrating the potential of recombinant NDV as a vaccine vector.

Recombinant Newcastle Disease Virus as a Vaccine Vector

1035. Syncytia Induction Enhances the Oncolytic Potential of Vesicular Stomatitis Virus in Virotherapy for Cancer

Rapid and accurate measurement of SARS-CoV-2 neutralizing antibodies (nAbs) can aid in understanding the development of immunity against COVID-19. This study evaluated the diagnostic performance of a rapid SARS-CoV-2 nAb detection test called the BZ COVID-19 nAb test BZ-nAb (BZ-nAb; BioZentech). Using the 90% plaque-reduction neutralization test (PRNT-90) as a reference, 104 serum specimens collected from COVID-19-positive and -negative patients were grouped into 40 PRNT-90-positive and 64 PRNT-90-negative specimens. The performance of the BZ-nAb was compared with that of the cPass surrogate virus neutralization test (cPass sVNT; Genscript). The BZ-nAb showed a sensitivity ranging from 92.5%–95.0% and specificity ranging from 96.9%–100%, whereas cPass sVNT showed a sensitivity of 100% (95% confidence interval (CI) 90.5%–100%) and specificity of 98.4% (95% CI, 91.6%–100%). The dilution factor obtained with PRNT-90 showed a stronger correlation with the percent inhibition of cPass sVNT (r = 0.8660, p < 0.001) compared with the test and control line ratio (T/C ratio) of the BZ-nAb (r = −0.7089, p < 0.001). An almost perfect agreement was seen between the BZ-nAb and cPass sVNT results, with a strong negative correlation between the BZ-nAb T/C ratio and cPass sVNT percent inhibition (r = −0.8022, p < 0.001). In conclusion, the diagnostic performance of the BZ-nAb was comparable to that of the cPass sVNT, although the BZ-nAb had a slightly lower sensitivity.

Man-Seong Park

Papers

Recombinant Newcastle Disease Virus as a Vaccine Vector

1035. Syncytia Induction Enhances the Oncolytic Potential of Vesicular Stomatitis Virus in Virotherapy for Cancer

Performance Evaluation of the BZ COVID-19 Neutralizing Antibody Test for the Culture-Free and Rapid Detection of SARS-CoV-2 Neutralizing Antibodies