SARS-CoV-2 RBD protein enhances the oncolytic activity of the vesicular stomatitis virus

Despite recent advances in the research on oncolytic viruses (OVs), a better understanding of how to enhance their replication is key to improving their therapeutic index. Understanding viral replication is important to improve treatment outcomes based on enhanced viral spreading within the tumor milieu. The VSV-Δ51 oncolytic virus has been widely used as an anticancer agent with a high selectivity profile. In this study, we examined the role of the SARS-CoV-2 spike protein receptor-binding domain (RBD) in enhancing VSV-Δ51 viral production and oncolytic activity. To test this hypothesis, we first generated a novel VSV-Δ51 mutant that encoded the SARS-COV-2 RBD and compared viral spreading and viral yield between VSV-Δ51-RBD and VSV-Δ51 in vitro. Using the viral plaque assay, we demonstrated that the presence of the SARS-CoV-2 RBD in the VSV-Δ51 genome is associated with a significantly larger viral plaque surface area and significantly higher virus titers. Subsequently, using an ATP release-based assay, we demonstrated that the SARS-CoV-2 RBD could enhance VSV-Δ51 oncolytic activity in vitro. This observation was further supported using the B16F10 tumor model. These findings highlighted a novel use of the SARS-CoV-2 RBD as an anticancer agent.Instituto de BiotecnologíaFil: Alkayyal, Almohanad A. University of Tabuk. Faculty of Applied Medical Sciences. Department of Medical Laboratory Technology; Arabia SauditaFil: Alkayyal, Almohanad A. King Abdullah International Medical Research Center. Immunology Research Program; Arabia SauditaFil: Ajina, Reham. King Abdullah International Medical Research Center. Immunology Research Program; Arabia SauditaFil: Ajina, Reham. King Saud bin Abdulaziz University for Health Sciences. College of Applied Medical Sciences. Department of Clinical Laboratory Sciences; Arabia SauditaFil: Cacciabue, Marco Polo Domingo. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Agrobiotecnología y Biología Molecular; ArgentinaFil: Cacciabue, Marco Polo Domingo. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Cacciabue, Marco Polo Domingo. Universidad Nacional de Luján. Departamento de Ciencias Básicas; ArgentinaFil: Alkayyal, Aaesha A. Taibah University. College of Medicine; Arabia SauditaFil: Saeedi, Nizar H. University of Tabuk. Faculty of Applied Medical Sciences. Department of Medical Laboratory Technology; Arabia SauditaFil: Hussain Alshehry, Taofik. Ministry of National Guard Health Affairs. King Saud University for Health Sciences. King Abdullah International Medical Research Centre; Arabia SauditaFil: Kaboha, Feras. Ministry of National Guard Health Affairs. King Saud University for Health Sciences. King Abdullah International Medical Research Centre; Arabia SauditaFil: Alotaibi, Mohammed A. University of Tabuk. Faculty of Applied Medical Sciences. Department of Medical Laboratory Technology; Arabia SauditaFil: Alotaibi, Mohammed A. Ministry of National Guard Health Affairs. King Saud University for Health Sciences. King Abdullah International Medical Research Centre; Arabia SauditaFil: Zaidan, Nada. King Abdulaziz City for Science and Technology. Joint Centers of Excellence Program. 8King Abdulaziz City for Science and Technology-Brigham and Women's Hospital (KACST-BWH) Centre of Excellence for Biomedicine; Arabia SauditaFil: Shah, Khalid. Harvard Medical School. Brigham and Women’s Hospital. Center for Stem Cell and Translational Immunotherapy (CSTI); Estados UnidosFil: Shah, Khalid. Harvard Medical School. Brigham and Women’s Hospital. Department of Neurosurgery; Estados UnidosFil: Shah, Khalid. Harvard University. Harvard Stem Cell Institute; Estados UnidosFil: Alroqi, Fayhan. King Abdullah International Medical Research Center. Immunology Research Program; Arabia SauditaFil: Alroqi, Fayhan. Ministry of the National Guard. Department of Immunology; Arabia SauditaFil: Alroqi, Fayhan. King Saud bin Abdulaziz University for Health Sciences. Faculty of Medicine; Arabia SauditaFil: Bakur Mahmoud, Ahmad. Taibah University. College of Applied Medical Sciences; Arabia SauditaFil: Bakur Mahmoud, Ahmad. Taibah University. Strategic Research and Innovation Laboratories; Arabia SauditaFil: Bakur Mahmoud, Ahmad. King Abdullah International Medical Research Center. Immunology Research Program; Arabia Saudit

Repurposing the oncolytic virus VSV∆51M as a COVID-19 vaccine

The coronavirus disease 2019 (COVID-19) pandemic imposes an urgent and continued need for the development of safe and cost-effective vaccines to induce preventive responses for limiting major outbreaks around the world. To combat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), we repurposed the VSV∆51M oncolytic virus platform to express the spike receptor-binding domain (RBD) antigen. In this study, we report the development and characterization of the VSV∆51M-RBD vaccine. Our findings demonstrate successful expression of the RBD gene by the VSV∆51M-RBD virus, inducing anti-RBD responses without attenuating the virus. Moreover, the VSV∆51M-RBD vaccine exhibited safety, immunogenicity, and the potential to serve as a safe and effective alternative or complementary platform to current COVID-19 vaccines

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival