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Tumor-Selective Oncolytic Vaccinia Virus and alphaDC1-Based Vaccine as a Combinat

肿瘤选择性溶瘤痘苗病毒和基于 alphaDC1 的疫苗作为组合

基本信息

批准号：
8518923
负责人：
DAVID L BARTLETT
金额：
$ 2.29万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-05 至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8518923
关键词：
Address Adoptive Cell Transfers Adoptive Transfer Animal Model Animals Anti-Inflammatory Agents Anti-inflammatory Antigens Autologous Binding Biodistribution Biological Assay Biopsy Specimen C57BL/6 Mouse CCL19 gene CCL22 gene CXCL11 gene Cancer Model Cancer Patient Cancer Vaccines Cell Maturation Cells Clinical Clinical Protocols Clinical Trials Coin Collaborations Colon Carcinoma Colorectal Cancer Combined Modality Therapy Cytotoxic T-Lymphocytes Data Data Analyses Dendritic Cell Vaccine Dendritic Cells Development Dose Effector Cell Engineering Environment Enzyme-Linked Immunosorbent Assay Eragrostis Gene Expression Genes Goals Human Image Immune Immune response Immunosuppressive Agents Immunotherapy Individual Infection Infiltration Inflammatory Infiltrate Inflammatory Response Injection of therapeutic agent Instruction Interferon-alpha Lead Malignant Neoplasms Mediating Messenger RNA Modeling Molecular Profiling Mus Mutation Natural Killer Cells Nature Neoplasm Metastasis Oncolytic Oncolytic viruses PTGS2 gene Paper Patients Pattern Phase Phase I Clinical Trials Physiologic pulse Positioning Attribute Principal Investigator Process Production Property Proteins Published Comment Publishing RANTES Randomized Recombinants Regimen Regulatory T-Lymphocyte Relative (related person)Research Personnel Role Running Serpins Specimen Staining method Stains Suggestion T-Lymphocyte Testing Th1 Cells Therapeutic Time Time Study Toxic effect Transgenes Transgenic Mice Tumor Immunity Tumor Tissue Vaccination Vaccines Vaccinia Vaccinia virus Vaccinium Vertebral column Viral Virus Writing anticancer research base cancer cell cancer immunotherapy cancer therapy celecoxib chemokine effective therapy experience improved in vitro Assay in vivo inhibitor/antagonist interest intravenous administration metastatic colorectal molecular imaging neoplastic cell novel strategies overexpression pre-clinical prevent programs response safety testing tool trafficking tumor vaccination strategy vector

项目摘要

Colorectal cancer is a relatively common malignancy with few curative options once metastases develop. Among the new approaches under development for further treatment of colorectal cancer patients are immunotherapy and oncolytic virotherapywhich show promising results in animal models. A newly developed unique dendritic cell (DC) maturation process produces highly activated DC's, coined aDC1. aDC1 vaccination has been particularly effective in animal models and in human clinical trials at producing high levels of circulating Tc1/Th1 anti-tumor effector cells. The next step in successful vaccination is to modify the tumor microenvironment to allow attraction of these circulating effector cells into the tumor. We and others have found that the chemokine milieu in the tumor microenvironment favors the attraction of Tc2/Th2 and Treg cells over Teff (Th1/Tc1) cells. Circulating cytotoxic T cells fail to traffic to the tumor environment and mediate an anti-tumor effect. Over the last 10 years, we have developed tumor-selective replicating recombinant vaccinia viruses (W) that effectively target tumor after systemic delivery, spread through the tumor, and express high levels of transgenes in the tumor environment. In this study, we propose to investigate the effects W has on the chemokine milieu in the tumor microenvironment, and investigate ways to improve the effects via mutation of immune relevant W genes and expression of selective Th1/Tc1-attracting or Treg-attracting chemokines from the tumor- targeted virus. The recombinant vaccinia serves two roles: as an oncolytic virus per se, and as a vector to express the Teff-attracting chemokines in the tumor tissue. Our hypothesis is that the combination of the two approaches would lead to a highly efficacious cancer therapy regimen for colorectal cancer. Specifically, we have three aims. Aim 1 is to determine the profile of chemokine expression and the composition of the inflammatory infiltrate in the tumor induced by recombinant, tumor-selective W. Aim 2 is to study the ability of the most promising W from Aim1 to enhance trafficking to the tumor of tumor-specific T cells derived from either adoptive cell transfer or aDC1 cancer vaccine, and to lead to improved anti-tumor response in combination therapy. And finally aim 3 will be performing a phase I clinical trial testing the safety and efficacy of a combination of aDC1 vaccination with systemic W administration in CRCpatients. RELEVANCE (See instructions):

结直肠癌是一种相对常见的恶性肿瘤，一旦发生转移，开发.在正在开发的进一步治疗结直肠癌的新方法中，患者的免疫治疗和溶瘤病毒治疗在动物中显示出有希望的结果模型一种新开发的独特的树突状细胞（DC）成熟过程产生高度的激活了DC，称为DC 1 aDC 1疫苗接种在动物模型中特别有效并在人体临床试验中产生高水平的循环Tc 1/Th 1抗肿瘤效应细胞。成功接种疫苗的下一步是修改肿瘤微环境以允许吸引这些循环效应细胞进入肿瘤。我们和其他人发现趋化因子肿瘤微环境中的环境有利于Tc 2/Th 2和Treg细胞的吸引超过Teff (Th1/Tc 1）细胞。循环的细胞毒性T细胞不能运输到肿瘤环境并介导肿瘤的发生。抗肿瘤作用在过去的10年里，我们已经开发了肿瘤选择性复制在全身递送后有效靶向肿瘤的重组牛痘病毒（W），并在肿瘤环境中表达高水平的转基因。在本研究中，我们建议研究W对肿瘤中趋化因子环境的影响，微环境，并研究通过免疫相关W 来自肿瘤的选择性Th 1/Tc 1-吸引或Treg-吸引趋化因子的基因和表达- 目标病毒重组牛痘有两个作用：本身作为溶瘤病毒，和作为免疫抑制剂。载体，以在肿瘤组织中表达吸引Tef的趋化因子。我们的假设是这两种方法的组合将导致高度有效的癌症治疗方案，结肠直肠癌具体来说，我们有三个目标。目的1：确定趋化因子的表达谱表达和组成的炎性浸润在肿瘤中诱导的重组，肿瘤选择性W.目的2是研究Aim 1中最有前途的W对增强来源于过继细胞转移或aDC 1的肿瘤特异性T细胞向肿瘤的运输癌症疫苗，并在联合治疗中导致改善的抗肿瘤反应。最后目标3将进行一项I期临床试验，测试联合使用 CRC患者中aDC 1疫苗接种与全身W给药。相关性（参见说明）：