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

Nat Commun. 2019 Jul 19;10(1):3236. doi: 10.1038/s41467-019-11137-5.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • Adenoviridae / immunology*
  • Animals
  • Antibodies / immunology*
  • Antibodies, Neutralizing / immunology
  • CD8-Positive T-Lymphocytes / immunology
  • Cell Line, Tumor
  • HEK293 Cells
  • Humans
  • Immunotherapy / methods*
  • Killer Cells, Natural / immunology
  • Mice
  • Molecular Targeted Therapy / methods
  • Neoplasms / immunology
  • Neoplasms / therapy*
  • Oncolytic Virotherapy / methods*
  • Oncolytic Viruses / genetics
  • Oncolytic Viruses / immunology*


  • Antibodies
  • Antibodies, Neutralizing