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Armed oncolytic parvoviral vectors for modulating the tumor microenvironment

用于调节肿瘤微环境的武装溶瘤细小病毒载体

基本信息

批准号：
9795232
负责人：
Peter J. Tattersall
金额：
$ 18.22万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-01 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9795232
关键词：
Adaptive Immune System Antibody Therapy Antigen-Presenting Cells Apoptosis Area Biological CD8-Positive T-Lymphocytes CD80 gene CTLA4 gene Capsid Cell Survival Cells Clinical Trials Cytotoxic T-Lymphocytes DNA cassette Disease Disease remission Dose Engineering Genome Germany Glioblastoma Homeostasis Human Immune Immune checkpoint inhibitor Immune signaling Immunotherapy In Vitro Individual Malignant Neoplasms Malignant neoplasm of pancreas Melanoma Cell Metastatic Melanoma Modeling Monoclonal Antibodies Mus Neoplasm Metastasis Oncolytic Oncolytic viruses Outcome Parvovirus Pathway interactions Penetration Phase Phenotype Production Property Proteins Risk Rodent SLEB2 gene System Testing Therapeutic Tissues Transgenes Tumor Antigens Tumor-Infiltrating Lymphocytes Virus anti-tumor immune response anticancer research base biological adaptation to stress design efficacy testing endoplasmic reticulum stress expression vector immune checkpoint immunogenic in vivo melanoma mouse model nanobodies neoplastic neoplastic cell preclinical efficacy preclinical evaluation public health relevance side effect tumor tumor microenvironment vector

项目摘要

Abstract: Armed oncolytic viruses are an emerging therapeutic strategy for many cancers. The parvoviruses are the smallest viruses currently being developed as oncotherapeutic agents, and are non-enveloped and extremely rugged, simplifying their production, purification and storage, as well as enhancing their tissue penetration properties. Rodent protoparvoviruses can infect human cells only if neoplastically transformed, and thus are intrinsically oncotropic - the rodent protoparvovirus H-1 is currently in Phase I/IIA clinical trials against glioblastoma and pancreatic cancer. We have developed a replicating, but non-propagating, parvoviral vector system, which can be packaged into tumor cell target-enhanced capsid selected in vitro. These dual transgene vectors express secreted, soluble versions of murine or human PD-1 (sPD-1), or an anti-CTLA-4 camelid nanobody, coordinately with the murine co-stimulatory molecules CD80 or CD48, to render the tumor cell itself an effective antigen presenting cell. We will test the hypothesis that the secreted transgene products will effectively block the two major immune checkpoint pathways when secreted directly within the tumor microenvironment, potentially avoiding the side-effects associated with systemic administration of immune checkpoint inhibitors.

摘要：中国武装溶瘤病毒是一种新兴的治疗多种癌症的新策略，而细小病毒则是主要的治疗策略。最小的病毒目前正在开发中，作为肿瘤治疗药物，病毒和病毒是非包膜病毒和极端病毒。坚固耐用，不仅简化了它们的生产、净化和储存，而且还增强了它们的组织渗透率。只有在肿瘤发生转化的情况下，这些啮齿动物和原病毒才能感染人类肝细胞，从而感染病毒。从本质上讲，嗜癌病毒是一种新的啮齿动物病毒H-1原病毒，目前正在进行针对该病毒的第I/IIA期临床试验。胶质母细胞瘤和胰腺癌。我们已经开发出一种可复制的、但非传播性的细小病毒载体。系统，它可以直接包装成肿瘤细胞和靶向增强型衣壳蛋白，并在体外选择细胞。转基因载体可表达分泌的、可溶的小鼠或人CD1抗体(SPD-1)或抗CTLA-4的抗体。骆驼的纳米体与小鼠的共刺激分子CD80或CD48协同作用，最终呈现出新的肿瘤。细胞本身是一种高效的抗原递呈细胞。我们将进一步验证这一假说，即人类分泌的是转基因生物的产物。当它们直接分泌到肿瘤内时，它将有效地阻断这两个主要的免疫系统检查点和通路。微环境，潜在地避免了与系统性免疫缺陷相关的副作用。检查站有抑制剂。