Oncolytic Newcastle-disease-virus-mediated CD47 blockade in preclinical melanoma and pancreatic cancer models.

Newcastle disease virus (NDV) exhibits strong immunostimulatory activity and a favorable safety profile, but its moderate monotherapy efficacy may be improved through combination therapies. Although NDV selectively infects and lyses tumor cells, viral infection unintentionally elevates tumor-cell CD47 expression-a "don't-eat-me" signal that could mask the full immunostimulatory potential of NDV. To offset this adverse host response, we engineered NDVs that expressed an anti-CD47 antibody or SIRPα-Fc immunoadhesin to pair direct oncolysis with local CD47 blockade to amplify SIRPα phagocytic-cell-mediated clearance of tumor cells and downstream antitumor immunity, as well as circumvent dose-related toxicities associated with systemic administration of CD47-blocking agents. NDV-mediated CD47 blockade decreased intratumoral CD47 expression and increased CD8 T cell activation, with no significant changes in antigen-presenting cell activation or phagocytosis. NDV-mediated CD47 blockade did not improve animal survival in B16-F10 melanoma nor KPC pancreatic ductal adenocarcinoma (PDAC), but greater incidence of tumor clearance resulting in immunological memory was observed in PDAC compared to B16-F10 tumor-bearing mice. Although NDV-mediated CD47 blockade resulted in increased numbers of PD-1 CD8 T cells, synergy between NDV, CD47, and PD-L1 blockade was limited. Together these data highlight the importance of considering tumor-intrinsic factors when combining cancer immunotherapies for improved outcomes.