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

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 adeno-
viruses 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 histo-
cultures, 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.