Molecular retargeting of antibodies converts immune defense against oncolytic viruses into cancer immunotherapy

Julia Niemann, Norman Woller, Jennifer Brooks, Bettina Fleischmann-Mundt, Nikolas T. Martin, Arnold Kloos, Sarah Knocke, Amanda M. Ernst, Michael P. Manns, Stefan Kubicka, Thomas C. Wirth, Rita Gerardy-Schahn and Florian Kühnel ()
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Julia Niemann: Medical School Hannover
Norman Woller: Medical School Hannover
Jennifer Brooks: Medical School Hannover
Bettina Fleischmann-Mundt: Medical School Hannover
Nikolas T. Martin: Medical School Hannover
Arnold Kloos: Medical School Hannover
Sarah Knocke: Medical School Hannover
Amanda M. Ernst: Medical School Hannover
Michael P. Manns: Medical School Hannover
Stefan Kubicka: Medical School Hannover
Thomas C. Wirth: Medical School Hannover
Rita Gerardy-Schahn: Medical School Hannover
Florian Kühnel: Medical School Hannover

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-11137-5

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