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.

抽象的：武装的溶瘤病毒是许多癌症的新兴理论策略。细小病毒是目前最小的病毒是作为耐疗法剂开发的，并且是非开发的，而且极其极端坚固，简化其生产，纯化和存储以及增强其组织穿透特性。啮齿动物原病毒只有在肿瘤转化时才能感染人类细胞，因此本质上是源自源自肿瘤 - 啮齿动物Protoparvoverus H -1目前正在I/IIA期临床试验中胶质母细胞瘤和胰腺癌。我们已经开发了一种复制但不propapag的山视伏载体矢量系统可以包装到体外选择的肿瘤细胞靶增强的衣壳中。这些双重转基因载体Express分泌，鼠或人PD-1（SPD-1）或抗CTLA-4的可溶性版本骆驼纳米机构，与鼠的共同刺激分子CD80或CD48协调细胞本身是有效的抗原呈现细胞。我们将测试分泌的转基因产品的假设直接在肿瘤内部分泌时，将有效阻止两个主要的免疫检查点途径微环境，有可能避免与全身给药有关的副作用检查点抑制剂。