An oncolytic vaccinia virus expressing anti-CD47 nanobody exerts enhanced antitumor activity by mediating innate and adaptive immune cell infiltration and activation in the lymphoma tumor microenvironment

作者：Mengyuan Li, Yinyin Zhang, Lihong Zong, Minghuan Zhang, Shibing Wang, Wen Lei, Wenbin Qian · 发表于：Haematologica · 年份：2025 · DOI：10.3324/haematol.2024.286923 · 被引用次数：7 · 研究领域：Virus-based gene therapy research、Phagocytosis and Immune Regulation、CAR-T cell therapy research

Anti-CD47 antibodies targeting macrophage immune checkpoints have demonstrated benefit in clinical trials, particularly in combination with targeted therapies. Nevertheless, this strategy faces challenges from suboptimal efficacy and on-target toxicity due to an immunosuppressive tumor microenvironment and ubiquitous CD47 expression. Here, we report a novel oncolytic vaccine virus (OVV) that expresses therapeutic transgenes encoding an anti-mouse CD47 nanobody or an anti-human CD47 nanobody fused with the IgG1 Fc fragment (termed OVV-mCD47nb and OVV-hCD47nb-G1, respectively), and show that anti-CD47 nanobodies secreted by lymphoma cells infected with armed OVV enhanced tumor phagocytosis via blockade of the CD47/SIRPα signal pathway. In an implanted subcutaneous lymphoma mouse model, OVV-mCD47nb demonstrated superior therapeutic efficacy and significantly prolonged survival of tumor-bearing mice when compared to its parental OVV, an effect which might be associated with the recruitment and activation of macrophages, natural killer cells, and T cells within the tumor microenvironment. Importantly, we discovered that the specific binding of secreted hCD47nb-G1 to CD47 enhanced macrophage-mediated tumor cell phagocytosis while sparing red blood cells. OVV-hCD47nb-G1 demonstrated superior antitumor efficacy compared to the anti-CD47 antibody Hu5F9 in lymphoma models. Both intratumoral and intraperitoneal administration of OVV-hCD47nb-G1 achieved significant tumor regression and p...