CD55-displaying oncolytic vaccinia virus treated metastatic cancers by evading the effect of host innate and adaptive humoral responses.

Abstract

Oncolytic viruses offer promising immunotherapy for cancer but face challenges such as delivery, targeting, and immune clearance. Our prior work showed that vaccinia virus (VACV) displaying the complement regulator CD55 evaded complement-mediated clearance, enhancing delivery and targeting in xenograft models. Importantly, this modified VACV also escaped neutralizing antibodies (NAbs) in vitro, a finding with significant implications. To improve translational relevance, we independently evaluated NAb evasion in immunocompetent in vivo models and against human-derived NAbs. Our novel platform virus, SJ-650-a CD55-displaying VACV expressing murine GM-CSF-retained superior antitumor efficacy despite the presence of NAbs in syngeneic breast cancer models. Additionally, SJ-650 effectively evaded NAbs derived from the serum of a clinical VACV trial (REN026). NAb evasion was CD55 dependent, occurred independently of complement activity, and was mediated by steric hindrance via the extracellular CD55 motif. NAb pretreatment masked binding of the key viral entry proteins A27, L1, and H3 in control viruses lacking CD55, but these interactions remained intact in SJ-650. By circumventing both complement and antibody responses, SJ-650 significantly inhibited tumor growth in two metastasis models, inducing immunogenic cell death and reprogramming the tumor microenvironment. These findings support SJ-650's potential as a robust oncolytic platform with broad translational applicability.