Clinical Trail of Vaccine in Combination with Toll-Like Receptor (TLR)

尽管癌症疫苗提供了巨大的希望，但临床有效性尚未实现。有效 疫苗可能需要包含免疫应答的基本要素， 病原体。现在很清楚，强烈的适应性免疫反应之前是一个强大的先天免疫系统。 免疫反应，由病原体相关分子模式（PAMP）触发， 表达Toll样受体（TLR）的免疫细胞。在没有TLR信号传导的情况下， 先天性免疫细胞的炎性细胞因子是次优的。肿瘤细胞通常不会触发TLR 信号传导，这导致实体瘤中缺乏有效的抗原特异性免疫。利用 而利用病原体所使用的机制来诱导有效的免疫， 改善抗原特异性抗肿瘤免疫应答的方法。浆细胞样树突状细胞， I型干扰素在体内的主要生产者，是抗病毒先天免疫的中心介质， 协调免疫细胞相互作用，导致有效的适应性T细胞反应。这种先天免疫 这种反应不仅对触发强T细胞启动很重要，而且对诱导靶点炎症也很重要 位点，其导致增强的T细胞迁移和效应器功能。在我们的小鼠模型中，我们发现 浆细胞样树突状细胞（pDC）可以导致增强的抗原特异性免疫应答，部分 通过与骨髓树突状细胞（mDC）的协同作用。此外，我们和其他人已经发现，pDC可以是 通过特异性TLR配体直接在体内激活。在本提案中，我们将测试这些概念， 并将利用疫苗与TLR激动剂的组合，所述TLR激动剂能够激活 pDC和mDC的协同作用，以便对在我们的鼠系统中观察到的协同作用进行建模。我们将测量T细胞的启动 在TLR活化存在或不存在的情况下免疫的患者中。在T细胞引发之后，我们将 在肿瘤部位施用TLR激动剂以诱导炎症。我们将测试这个的能力 干预以激活肿瘤部位的pDC和mDC并增强T细胞向肿瘤和T细胞中的迁移 效应子功能具体而言，我们将：1）在存在免疫抑制剂的情况下评估免疫后的T细胞引发。 2）分析TLR后的肿瘤微环境 3）将临床应答与T细胞引发和活化状态相关联 肿瘤微环境中的免疫细胞。通过应用从我们的基本 理解在成功控制病毒感染期间TLR信号传导促进的免疫反应， 我们的目标是开发改进的抗肿瘤反应。此外，这些研究可能会导致战略， 其可以推广到改进针对其他常见癌症的癌症疫苗。

Although cancer vaccines offer significant promise, clinical effectiveness has yet to be realized. Effective vaccines may require inclusion of basic elements of the immune response which allow successful elimination of pathogens. It is now clear that strong adaptive immune responses are preceded by a potent innate immune response, triggered by pathogen-associated molecular patterns (PAMPs) that are recognized by immune cells expressing Toll-like receptors (TLRs). In the absence of TLR signaling, release of inflammatory cytokines by innate immune cells is sub-optimal. Tumor cells typically do not trigger TLR signaling and this contributes to the lack of effective antigen-specific immunity in solid tumors. Harnessing and adapting the mechanisms used by pathogens to induce effective immunity represents a very promising approach to improving antigen-specific antitumor immune responses. The plasmacytoid dendritic cell, the primary producer of type I interferons in the body, is a central mediator of anti-viral innate immunity and coordinates immune cell interactions which lead to a potent adaptive T-cell response. This innate immune response is important not only to trigger strong T-cell priming, but also to induce inflammation at the target site which leads to enhanced T-cell migration and effector function. In our murine models, we have found that plasmacytoid dendritic (pDC) cells can lead to enhanced antigen-specific immune responses, partially through synergy with myeloid dendritic cells (mDC). In addition, we and others have found that pDC can be activated directly in vivo through specific TLR ligands. In this proposal, we will test these concepts in melanoma patients and will utilize a vaccine in combination with a TLR agonist capable of activating both pDC and mDC in order to model the synergy observed in our murine system. We will measure T-cell priming in patients immunized in the presence or absence of TLR activation. Subsequent to T-cell priming, we will administer a TLR agonist at the tumor site in order to induce inflammation. We will test the ability of this intervention to activate pDC and mDC at the tumor site and enhance T-cell migration into the tumor and Tcell effector function. Specifically, we will: 1) Evaluate T-cell priming following immunization in the presence or absence of TLR activation at the vaccine site, 2) Analyze the tumor microenvironment following TLR administration at the tumor site, and 3) Correlate clinical response with T-cell priming and the activation state of immune cells within the tumor microenvironment. By applying principles learned from our basic understanding of immune reactions facilitated by TLR signaling during successfully controlled viral infections, our goal is to develop improved antitumor responses. In addition, these studies may lead to strategies which may be generalized towards improving cancer vaccines against other common cancers.