Fig. 6: Treatment of tumour-bearing mice with VV-αHER2-TCE and VSVΔ51-HER2T prolongs overall survival and reduces lung metastases in disseminated disease models.

a Experimental overview: 5 \(\times\) 10⁵ 4T1.2 cells were injected i.v. by teil vein injection into BALB/c mice, and treated as indicated, followed by harvest and staining of lungs. b Following staining with black India ink, lungs were fixed and imaged. c Metastatic lung nodules were quantified. Shown are mean ± SEM, n = 10 mice in the PBS group, n = 5 mice in all other groups; P-value calculated by one-way ANOVA relative to VSVΔ51-HER2T, with Dunnett correction for multiple comparisons. d Experimental overview: 5 \(\times\) 10⁶ ID8-PP cells were implanted i.p. in C57BL/6 mice, followed by treatments as indicated. e Overall survival was monitored; P-values indicated next to treatment groups is relative to VSVΔ51-HER2T+VV-αHER2-TCE. For analysis of survival data, P-values were calculated by the Kaplan–Meier method followed by log-rank test. Source data are provided as a Source Data file. f Schematic depicting the dual oncolytic virus approach to treat tumours (indicated by the number 1), whereby VSVΔ51 and VV produce the HER2T synthetic target and its cognate TCE, respectively. These two OVs synergize since VV dampens interferon levels and increases VSVΔ51 replication. VV-produced TCEs recognize and bind to HER2T, forming a pseudo-immunological synapse that allows for the release of effector molecules (e.g. granzyme, perforin). OVs lead to the recruitment of immune cells in the tumour, and TCEs mediate the activation of T cells that trigger apoptosis of cancer cells. Ultimately, this strategy improves survival of mice bearing different tumour types and decreases lung metastases. Importantly, VSVΔ51-mediated production of HER2T on the surface of cancer cells can synergize with other alternative antibody-based approaches, such as antibody-drug conjugates like T-DM1 (indicated by the number 2). In this case, the ADC can synergize with VSVΔ51 to promote viral replication. The ADC-mediated cell death also leads to increased survival in preclinical animal models and decreased lung metastases in mice.