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，一旦转移，治疗方案很少。 发展。正在开发的进一步治疗结直肠癌的新方法中 患者正在接受免疫治疗和溶瘤病毒治疗，这些治疗在动物身上显示出有希望的结果 模特们。一种新开发的独特的树突状细胞(DC)成熟过程产生了 激活了DC，创造了aDc1。ADC1疫苗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Tc1/Th1抗肿瘤效应细胞。 成功接种疫苗的下一步是改变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Tc2/Th2和Treg细胞对T细胞的吸引 (Th1/Tc1)细胞。循环中的细胞毒性T细胞不能运输到肿瘤环境并介导 抗肿瘤作用。在过去的10年里，我们开发了肿瘤选择性复制 重组痘苗病毒(W)在全身递送、传播后有效靶向肿瘤 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，并探索通过免疫相关W突变来提高疗效的途径 肿瘤特异性Th1/Tc1趋化因子的基因和表达 目标病毒。重组牛痘有两种作用：作为溶瘤病毒本身和作为一种 载体在肿瘤组织中表达诱人趋化因子。我们的假设是 这两种方法的结合将导致一种高效的癌症治疗方案 结直肠癌。具体地说，我们有三个目标。目的1是确定趋化因子的分布 重组人T细胞在肿瘤中的表达及炎性浸润物的组成 肿瘤选择性W。目的2研究Aim1中最有希望的W增强 过继细胞转移或aDC1来源的肿瘤特异性T细胞向肿瘤的转运 癌症疫苗，并导致在联合治疗中改善抗肿瘤反应。最后， Aim 3将进行一项I期临床试验，测试联合应用 慢性粒细胞白血病患者全身注射ADC1疫苗。 相关性(请参阅说明)：

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):