肿瘤细胞治疗研究
英文原题：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.
靶向巨噬细胞免疫检查点的抗CD47抗体已在临床试验中显示出获益，尤其是在与靶向治疗联合应用时。
靶向巨噬细胞免疫检查点的抗CD47抗体已在临床试验中显示出获益，尤其是与靶向治疗联合使用时。然而，由于免疫抑制性肿瘤微环境和CD47的广泛表达，该策略面临疗效欠佳和靶向毒性的挑战。在此，我们报道了一种新型溶瘤疫苗病毒（OVV），其表达编码抗小鼠CD47纳米抗体或融合IgG1 Fc片段的抗人CD47纳米抗体的治疗性转基因（分别称为OVV-mCD47nb和OVV-hCD47nb-G1），并表明被武装OVV感染的淋巴瘤细胞所分泌的抗CD47纳米抗体通过阻断CD47/SIRPα信号通路增强肿瘤吞噬作用。在植入性皮下淋巴瘤小鼠模型中，与亲本OVV相比，OVV-mCD47nb表现出更优的治疗疗效，并显著延长荷瘤小鼠的生存期，这一效应可能与肿瘤微环境中巨噬细胞、NK 细胞和T细胞的募集和激活有关。重要的是，我们发现分泌的hCD47nb-G1与CD47的特异性结合增强了巨噬细胞介导的肿瘤细胞吞噬作用，同时不损伤红细胞。在淋巴瘤模型中，OVV-hCD47nb-G1表现出优于抗CD47抗体Hu5F9的抗肿瘤疗效。OVV-hCD47nb-G1的瘤内和腹腔给药均实现了显著的肿瘤消退和生存期延长，其机制可能通过增强免疫细胞激活而重编程肿瘤微环境。值得注意的是，与CD19 CAR-T联合使用可通过克服CAR-T细胞浸润受限这一关键障碍，协同改善皮下淋巴瘤的治疗效果。我们的研究结果表明，用CD47阻断纳米抗体和IgG1 Fc武装OVV可构建一种双功能治疗平台，通过协调固有免疫和适应性免疫激活，为淋巴瘤免疫治疗提供一种范式转变策略。
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 prolonged survival, potentially through tumor microenvironment reprogramming via enhanced immune cell activation. Notably, combination with CD19 chimeric antigen receptor T cells synergistically improved therapeutic outcomes in subcutaneous lymphomas by overcoming the critical barrier of limited chimeric antigen receptor T-cell infiltration. Our findings establish that arming OVV with a CD47-blocking nanobody and IgG1 Fc creates a dual-functional therapeutic platform, offering a paradigm-shifting strategy for lymphoma immunotherapy through coordinated innate and adaptive immune activation.
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