To overcome virus-neutralizing antibody interference in oncolytic virotherapy, Niemann et al. developed an adaptor molecule consisting of DE1 (a common target domain on adenovirus) and an scFv targeting polysialic acid on tumor cells to redirect anti-DE1 antibodies to tumors. In several Ad5-immunized tumor-bearing mouse models, including one of disseminated disease, DE1scFv-pSia reduced tumor growth and prolonged survival, dependent on NK cells and subsequent induction of tumor-specific CD8+ T cell responses. DE1scFv-pSia synergized with oncolytic adenoviral therapy and PD-1 checkpoint blockade, especially in the triple combination.
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Virus-neutralizing antibodies are a severe obstacle in oncolytic virotherapy. Here, we present a strategy to convert this unfavorable immune response into an anticancer immunotherapy via molecular retargeting. Application of a bifunctional adapter harboring a tumor-specific ligand and the adenovirus hexon domain DE1 for engaging antiadenoviral antibodies, attenuates tumor growth and prolongs survival in adenovirus-immunized mice. The therapeutic benefit achieved by tumor retargeting of antiviral antibodies is largely due to NK cell-mediated triggering of tumor-directed CD8 T-cells. We further demonstrate that antibody-retargeting (Ab-retargeting) is a feasible method to sensitize tumors to PD-1 immune checkpoint blockade. In therapeutic settings, Ab-retargeting greatly improves the outcome of intratumor application of an oncolytic adenovirus and facilitates long-term survival in treated animals when combined with PD-1 checkpoint inhibition. Tumor-directed retargeting of preexisting or virotherapy-induced antiviral antibodies therefore represents a promising strategy to fully exploit the immunotherapeutic potential of oncolytic virotherapy and checkpoint inhibition.