Tumor microenvironment remodeling by an engineered oncolytic adenovirus results in improved outcome from PD-L1 inhibition

Oncoimmunology. 2020 May 22;9(1):1761229. doi: 10.1080/2162402X.2020.1761229.


Checkpoint inhibitors have revolutionized cancer therapy and validated immunotherapy as an approach. Unfortunately, responses are seen in a minority of patients. Our objective is to use engineered adenoviruses designed to increase lymphocyte trafficking and cytokine production at the tumor, to assess if they increase the response rate to checkpoint inhibition, as these features have been regarded as predictive for the responses. When Ad5/3-E2F-d24-hTNFa-IRES-hIL2 (an oncolytic adenovirus coding for TNFa and IL-2, also known as TILT-123) and checkpoint inhibitors were used together in fresh urological tumor histocultures, a significant shift toward immune activity (not only tumor necrosis alpha and interleukin-2 but also interferon gamma and granzyme B) and increased T-cell trafficking signals (CXCL10) was observed. In vivo, our viruses enabled an anti-PD-L1 (a checkpoint inhibitor) delivering complete responses in all the treated animals (hazard ratios versus anti-PD-L1 alone 0.057 [0.007; 0.451] or virotherapy alone 0.067 [0.011; 0.415]). To conclude, when an engineered oncolytic adenovirus was utilized to modify the tumor microenvironment towards what meta-analyses have pointed as predictive markers for checkpoint inhibitory therapy, the response to them increased synergistically. Of note, key findings were confirmed in fresh patient-derived tumor explants.

Keywords: Oncolytic virus; adenovirus; checkpoint inhibitors; immunotherapy; tumor microenvironment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • B7-H1 Antigen / genetics
  • Humans
  • Oncolytic Virotherapy*
  • Oncolytic Viruses* / genetics
  • Tumor Microenvironment


  • B7-H1 Antigen

Grant support

This study was supported by Marie Skłodowska-Curie Innovative Training Networks (ITN-EID VIRION H2020-MSCA-ITN-2014 project number 643130), Jane and Aatos Erkko Foundation, HUCH Research Funds (EVO), Sigrid Juselius Foundation, Finnish Cancer Organizations, University of Helsinki, Novo Nordisk Foundation, Päivikki and Sakari Sohlberg Foundation, The Finnish Society of Sciences and Letters, and TILT Biotherapeutics Ltd.