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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：武装溶瘤病毒是许多癌症的新兴治疗策略。最小的病毒，目前正在开发的肿瘤治疗剂，是非包膜和极端坚固耐用，简化了其生产，纯化和储存，并增强了其组织渗透性特性. 啮齿动物原细小病毒只有在肿瘤性转化时才能感染人细胞，因此，啮齿动物原细小病毒H-H1目前正处于I/IIA期临床试验，我们已经开发了一种复制型，但非增殖型的细小病毒载体，系统，其可以包装到体外选择的肿瘤细胞靶向增强衣壳中。这些双重转基因载体表达分泌的可溶性鼠或人PD-11（sPD-11）或抗PD-CTLA-14，骆驼科纳米抗体，与鼠共刺激分子CD 80或CD 48协同，使肿瘤细胞本身是一个有效的抗原呈递细胞。我们将检验分泌的转基因产物当直接在肿瘤内分泌时，微环境，潜在地避免与全身施用免疫调节剂相关的副作用。检查点抑制剂。