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 (177Lu-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 64Cu-aPD-L1 accumulation in tumor tissues. HY-oAd in combination with either aPD-L1 or 177Lu-aPD-L1 (HY-oAd+aPD-L1 or HY-oAd+177Lu-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 177Lu-aPD-L1 in a multifaceted manner to elicit synergistic antitumor immune response against desmoplastic and poorly immunogenic pancreatic tumors.