A CD47-blocking oncolytic vaccinia virus for cancer therapy

用于癌症治疗的阻断 CD47 的溶瘤痘苗病毒

• 批准号: 9256220
• 负责人: Felicia Cao
• 金额: $ 4.4万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-18 至 2019-03-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9256220
• 关键词: Adverse effects; Affinity; Antigen-Presenting Cells; Antitumor Response; Biological Response Modifier Therapy; Bystander Effect; CD47 gene; Cells; Clinical Research; Genome; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Hematologic Neoplasms; IgG4; Immune; Immune response; Immunosuppressive Agents; In Vitro; In complete remission; Infusion procedures; Killer Cells; Late Promoters; Light; Measurement; Modeling; Mus; Oncolytic; Oncolytic viruses; Patient-Focused Outcomes; Patients; Phagocytes; Phagocytosis; Phase; Pre-Clinical Model; Production; Proteins; Recurrence; Refractory; Research; Risk; SILV gene; Safety; Signal Transduction; Site; Solid Neoplasm; Survival Analysis; T cell response; T-Lymphocyte; Testing; Time; Transcriptional Regulation; Tumor Antigens; Vaccinia; Vaccinia virus; Virus Replication; antitumor effect; cancer therapy; cell killing; conventional therapy; cytokine; cytotoxic; experimental study; improved outcome; in vivo; killings; macrophage; melanoma; neoplastic cell; novel; novel therapeutics; outcome forecast; public health relevance; safety study; tumor; tumor growth; tumor microenvironment

 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.

 描述（由申请人提供） 该项目的长期目标是开发一种新的溶瘤痘苗病毒（VV）用于治疗晚期实体瘤。晚期实体瘤患者的预后仍然很差，生物疗法（如VV）有可能改善预后。虽然VV在早期临床研究中显示出有希望的抗肿瘤活性，但很少有患者被治愈。这种疗效的缺乏很可能是由于VV无法杀死所有肿瘤 细胞和/或诱导有效的抗肿瘤免疫应答。肿瘤相关巨噬细胞（TAM）是促进肿瘤生长和创造免疫抑制肿瘤微环境的关键参与者。然而，最近的研究表明，TAM的固有吞噬能力可以通过阻断肿瘤细胞上的CD 47并使用由SIRPα的高亲和力胞外结构域融合到IgG 4的Fc区（SIRPα-Fc）组成的嵌合分子提供调理信号来诱导抗肿瘤反应。我们现在建议将这种方法应用于溶瘤VV，并假设经遗传修饰以表达SIRPα-Fc的溶瘤VV（SIRPα-Fc-VV）与未修饰的VV相比具有增强的抗肿瘤活性。SIRPα-Fc的局部产生也应该上级于蛋白质的间歇性直接输注，因为SIRPα-Fc的浓度在肿瘤部位应该最高，并且因为它降低了与SIRPα-Fc的全身施用相关的不希望的副作用的风险。由于巨噬细胞是有效的抗原呈递细胞，我们进一步假设SIRPα-Fc-VV诱导的巨噬细胞吞噬肿瘤细胞将导致诱导肿瘤相关抗原（TAA）特异性T细胞。我们建议测试 我们的假设在2个相互关联的研究目标。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2将评价SIRPα-Fc-VV和SIRPα-VV在B16黑色素瘤模型中的抗肿瘤活性，并评估其诱导B16 TAA特异性T细胞应答的能力。如果成功，这种方法可以很容易地应用于目前正在开发的用于广泛的实体瘤的溶瘤病毒。