Oncolytic adenovirus in combination with PD-L1-targeted radioimmunotherapy exerts synergistic antitumor effect against pancreatic cancer

Background To date, no radioimmunotherapy (RIT) regimen has been approved by US Food and Drug Administration for the treatment of pancreatic cancers. Highly desmoplastic and immune-desert phenotypes of pancreatic cancer remain two major hurdles that attenuate the efficacy of conventional treatment (radiotherapy and chemotherapy) and immunotherapeutic (immune checkpoint inhibitors and chimeric antigen receptor T cells). Method To overcome these hurdles, an oncolytic adenovirus (oAd) co-expressing interleukin-12, granulocyte macrophage colony-stimulating factor, and relaxin (HY-oAd) was investigated in combination with programmed death-ligand 1 (PD-L1)-targeted RIT (lutetium-177-labeled atezolizumab ( 177 Lu-aPD-L1)). Results HY-oAd treatment was shown to elevate PD-L1 expression level and promoted degradation of extracellular matrix of pancreatic tumors, resulting in increased aPD-L1 or 64 Cu-aPD-L1 accumulation in tumor tissues. HY-oAd in combination with either aPD-L1 or 177 Lu-aPD-L1 (HY-oAd+aPD-L1 or HY-oAd+ 177 Lu-aPD-L1, respectively) elicited more potent antitumor effect against the pancreatic tumors than respective monotherapy in both subcutaneous and orthotopic pancreatic tumor models. The potent antitumor effect of HY-oAd+aPD-L1 combination therapy was due to superior intratumoral infiltration and activation of dendritic cells and CD4 + or CD8 + T cells over the respective monotherapy. Conclusion Collectively, our findings demonstrate that HY-oAd can enhance intratumoral accumulation of 177 Lu-aPD-L1 in a multifaceted manner to elicit synergistic antitumor immune response against desmoplastic and poorly immunogenic pancreatic tumors.