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

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，被称为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）：

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):