A CD47-blocking oncolytic vaccinia virus for cancer therapy

 描述(由申请人提供) 该项目的长期目标是开发一种新型的溶瘤牛痘病毒(VV)，用于治疗晚期实体瘤。晚期实体瘤患者的预后仍然很差，VVS等生物疗法有可能改善预后。虽然VVS在早期临床研究中显示出良好的抗肿瘤活性，但很少有患者被治愈。这种效果的缺乏很可能是由于VVS不能杀死所有的肿瘤 细胞和/或诱导有效的抗肿瘤免疫反应。肿瘤相关巨噬细胞(TAMs)在促进肿瘤生长和创造免疫抑制的肿瘤微环境中起着关键作用。然而，最近的研究表明，TAMs固有的吞噬能力可以通过阻断肿瘤细胞上的CD47来诱导抗肿瘤反应，并利用由Sirpα的高亲和力胞外区与Ig G4Fc区融合的嵌合分子(Sirpα-Fc)来提供调理信号。我们现在建议将这种方法应用于溶瘤VV，并假设经基因改造表达Sirpα-Fc(α-Fc-Vv)的溶瘤Vv与未修饰的Vv相比具有更强的抗肿瘤活性。局部生产Sirpα-FC也应优于间歇直接输注蛋白质，这既是因为Sirpα-FC在肿瘤部位的浓度应该是最高的，也是因为它降低了与全身应用Sirpα-FC相关的不良副作用的风险。由于巨噬细胞是强大的抗原提呈细胞，我们进一步假设α-Fc-Vv诱导的巨噬细胞吞噬肿瘤细胞将导致肿瘤相关抗原特异性T细胞的诱导。我们打算测试一下 我们的假设有两个相互关联的研究目的。目的1制备Sirpα-Fc-Vv和Sirpα-Vv，并比较它们在肿瘤细胞中的复制能力和体外激活巨噬细胞的能力。目的评价Sirpα-Fc-Vv和Sirpα-Vv在B16黑色素瘤模型中的抗肿瘤活性，并评价它们诱导B16TAA特异性T细胞反应的能力。如果成功，这种方法可以很容易地应用于溶瘤病毒，目前正在开发用于广泛的实体肿瘤。

 DESCRIPTION (provided by applicant) The long-term goal of this project is to develop a novel oncolytic vaccinia virus (VV) for the treatment of advanced stage solid tumors. The prognosis for patients with advanced stage solid tumors remains poor and bio-therapeutics such as VVs have the potential to improve outcomes. While VVs have shown promising antitumor activity in early Phase clinical studies, few patients have been cured. This lack of efficacy is most likely due to the inability of VVs to kill all tumor cells and/or induce effective antitumoral immune responses. Tumor associated macrophages (TAMs) are key players in promoting tumor growth and creating an immunosuppressive tumor microenvironment. However, recent studies have shown that the inherent phagocytic capacity of TAMs can be harnessed to induce antitumor responses by blocking CD47 on tumor cells and provision of an opsonization signal using a chimeric molecule that consists of the high affinity ectodomain of SIRPα fused to the Fc region of IgG4 (SIRPα-Fc). We now propose to adapt this approach to oncolytic VVs and hypothesize that an oncolytic VV that is genetically modified to express SIRPα-Fc (SIRPα-Fc-VV) will have enhanced antitumor activity in comparison to unmodified VV. Local production of SIRPα-Fc should also be superior to the intermittent direct infusion of the protein, both because the concentration of SIRPα-Fc should be highest at the sites of tumor and because it reduces the risks of unwanted side effects associated with the systemic administration of SIRPα-Fc. Since macrophages are potent antigen presenting cells, we hypothesize further that SIRPα-Fc-VV-induced phagocytosis of tumor cells by macrophages will result in the induction of tumor associated antigen (TAA)-specific T cells. We propose to test our hypotheses in 2 interrelated research aims. Aim 1 generates SIRPα-Fc-VV and SIRPα-VV, and compares their ability to replicate in tumor cells and activate macrophages in vitro. Aim 2 will then evaluate the antitumor activity of SIRPα-Fc-VV and SIRPα-VV in the B16 melanoma model, and assess their ability to induce B16 TAA-specific T-cell responses. If successful, this approach could be readily applied to oncolytic viruses that are currently being developed for a broad range of solid tumors.