An Engineered Self-biomineralized Oncolytic Adenovirus Induces Effective Antitumor Immunity and Synergizes With Immune Checkpoint Blockade.

Abstract

Oncolytic adenoviruses (oADV) are promising cancer treatment agents. However, in vivo hepatic sequestration and the host immunologic response against the agents limit the therapeutic potential of oADVs. In this study, we present a combined method with a rational design for improving oADV infection efficiency, immunogenicity, and treatment efficacy by self-biomineralization. We integrated the biomimetic nucleopeptide W6p into the capsid of oADV using reverse genetics, allowing calcium phosphate mineralization to be biologically induced on the surface of oADV under physiologic conditions, resulting in a mineral exterior. This self-biomineralized, modified oADV (oADV-W6-CaP) enhanced infection efficiency and therapeutic efficacy in coxsackievirus and adenovirus receptor (CAR)-negative cancer cells wherein protecting them against neutralization by preexisting neutralizing antibodies. In subcutaneous mouse tumor models, systemic injection of oADV-W6-CaP demonstrated improved antitumor effectiveness, which was associated with increased T-cell infiltration and CD8+ T-cell activation. In addition, the anticancer immune response elicited by oADV-W6-CaP was dependent on CD8+ T cells, which mediated long-term immunologic memory and systemic antitumor immunity against the same tumor. Finally, the addition of PD1 or CD47 inhibition boosted the anticancer effects of oADV-W6-CaP and increased the rate of complete tumor clearance in tumor-bearing animals. The self-biomineralized oADV shifted the suppressive tumor microenvironment from a "cold" to "hot" state and synergized with immune checkpoint blockade to exert outstanding tumoricidal effects, demonstrating promising potential for cancer immunotherapy.