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，几乎没有治愈的选择发展。在开发的新方法中，用于进一步治疗结直肠癌患者是免疫疗法和溶瘤病毒疗法，在动物中表现出令人鼓舞的结果型号。新开发的独特的树枝状细胞（DC）成熟过程高度产生激活的DC，创建的ADC1。 ADC1疫苗接种在动物模型中特别有效在人类临床试验中，生产高水平的循环TC1/TH1抗肿瘤效应细胞。成功疫苗接种的下一步是修改肿瘤微环境以允许吸引力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TC2/TH2和Treg细胞的吸引（TH1/TC1）细胞。循环的细胞毒性T细胞无法访问肿瘤环境并介导抗肿瘤效应。在过去的十年中，我们开发了肿瘤选择性复制重组疫苗病毒（W），该病毒在全身分娩后有效靶向肿瘤，扩散通过肿瘤，并在肿瘤环境中表达高水平的转基因。在这项研究中，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的突变改善影响的方法选择性Th1/Tc1吸引或提取Treg的趋化因子的基因和表达靶向病毒。重组疫苗有两个角色：作为溶瘤病毒本身，作为一个向量表达肿瘤组织中吸引TEFF的趋化因子。我们的假设是两种方法的结合将导致高效的癌症治疗方案结直肠癌。具体来说，我们有三个目标。目标1是确定趋化因子的曲线重组诱导的肿瘤中炎症性浸润的表达和组成，肿瘤选择性W. AIM 2是研究AIM1最有希望的W的能力以增强贩运源自产卵细胞转移或ADC1的肿瘤特异性T细胞的肿瘤癌症疫苗，并导致联合疗法中的抗肿瘤反应改善。最后 AIM 3将进行I期临床试验，以测试组合的安全性和功效 ADC1疫苗接种与CRCPATENT的全身W给药。相关性（请参阅说明）：