In-situ activation of anti-tumor effectors

虽然疫苗策略在患者产生肿瘤特异性免疫方面继续有很大的优势 承诺，到目前为止，它们在抗肿瘤功效方面还没有达到压倒性的效果。来自我们的研究和 其他实验室已经检查了对肿瘤缺乏明显的免疫识别和有限的有效性。 基于肿瘤抗原的疫苗。在该奖项资助的最后一期资金中，我们的研究 利用四聚体分析，对肿瘤相关人群、淋巴结和全身人群进行功能评估 以及一系列表位特异性疫苗的产生，导致了我们对活性免疫的定义 肿瘤微环境和引流层粘连蛋白表现出平衡的逃逸机制 效应器和调节细胞导致外周的功能性无能。 我们的基本假设/策略是，通过调节肿瘤微环境，我们将能够 诱导有效的肿瘤特异性全身反应。我们将重点介绍使用原位基因转移的方法 痘病毒重组体，因为我们相信这将为我们提供一个最佳免疫的机会 肿瘤相关抗原的结合。我们的发现，局部免疫调节可以导致外周 响应性使我们假设，地方干预有可能增强对 在外周给予肿瘤抗原编码疫苗，从而增强系统效应器功能。因此， 虽然大家都清楚地认为，发展系统反应能力是至关重要的，但如果 我们的研究表明，肿瘤微环境阻碍了有效的全身系统的发展 免疫，甚至更糟，建立了一种环境，在这种环境中，免疫实际上阻碍了预期的反应 通过我们所描述的负调控成分的扩展，调节肿瘤-宿主环境 可能在诱导有效的抗肿瘤免疫中起关键作用。我们将：1.描述肿瘤的特征 微环境/引流淋巴结/和全身免疫轴作为进一步识别的手段 使用痘苗病毒重组体的操纵目标：将肿瘤微环境作为工厂 全身性无反应性；2.评估肿瘤-DLN中抗原提呈的局部调节 增强抗肿瘤反应的隔室；3.评估Treg和效应器的局部调制 使用基于受体和基于抗体的基因融合分子作为疫苗的辅助成分的功能； 用抗体和小分子评价肿瘤诱导调节机制的系统调节 作为疫苗的辅助物。

While vaccine strategies for the generation of tumor specific immunity in patients continue to have great promise, to date they have been less than overwhelming in their antitumor efficacy. Studies from our and other laboratories have examined the lack of apparent immune recognition of tumor and limited effectiveness of tumor antigen based vaccines. During the last period of funding supported by this award, our studies utilizing tetramer analysis, functional assessment of tumor associated, lymph node, and systemic populations and the generation of a family of epitope specific vaccines, have resulted in our defining an active immune escape mechanism in which the tumor microenvironment and draining LN manifest a balance between effector and regulatory cells resulting in functional anergy in the periphery. Our underlying hypothesis/strategy is that by modulating the tumor microenvironment we will be able to induce an effective tumor specific systemic response. We will focus on the use of in-situ gene transfer using poxvirus recombinants, as we believe this will provide us an opportunity to immunize to the optimal combination of tumor-associated antigens. Our findings that local immune modulation can lead to peripheral responsiveness has led us to hypothesize that local intervention has the potential to enhance the response to tumor antigen encoding vaccines given in the periphery thus enhancing systemic effector function. Thus, while there is clear agreement that the development of systemic responsiveness is crucial, if what goes on in the tumor microenvironment, as our studies have shown, blocks the development of effective systemic immunity or even worse, sets up an environment where immunization actually hinders the desired response via the expansion of a negative regulatory component as we describe, modulating the tumor-host environment may be critical in inducing effective antitumor immunity. We will: 1. Characterize the tumor microenvironment / draining lymph node / and systemic immunity axis as a means of further identifying targets for manipulation using vaccinia virus recombinants: "The tumor microenvironment as a "factory" for systemic unresponsiveness"; 2. Evaluate localized modulation of antigen presentation in the tumor-DLN compartment for enhanced antitumor responses; 3. Evaluate localized modulation of Treg and effector functions using receptor-based and antibody-based genetic fusion molecules as adjuncts to vaccines; and 4. Evaluate systemic modulation of tumor-induced regulatory mechanisms using antibodies and small molecules as adjuncts to vaccines.