In-situ activation of anti-tumor effectors

虽然用于在患者中产生肿瘤特异性免疫的疫苗策略仍然具有很大的优势， 但是，迄今为止，它们在抗肿瘤功效方面还不那么压倒性。我们的研究和 其他实验室已经检查了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段时间里，我们的研究 利用四聚体分析、肿瘤相关、淋巴结和全身群体的功能评估 以及表位特异性疫苗家族的产生，导致我们定义了一种主动免疫， 逃逸机制，其中肿瘤微环境和引流LN表现出平衡， 效应细胞和调节细胞导致外周功能性无反应性。 我们的基本假设/策略是，通过调节肿瘤微环境，我们将能够 诱导有效肿瘤特异性全身反应。我们将重点介绍使用原位基因转移， 痘病毒重组，因为我们相信这将为我们提供一个机会，免疫的最佳 肿瘤相关抗原的组合。我们的研究结果表明，局部免疫调节可以导致外周 反应性使我们假设，地方干预有可能提高对 在外周给予编码肿瘤抗原的疫苗，从而增强全身效应子功能。因此，在本发明中， 虽然有明确的共识，发展系统的反应能力是至关重要的，如果发生在 正如我们的研究所示，肿瘤微环境阻碍了有效的系统性肿瘤的发展。 甚至更糟的是，建立了一种环境，在这种环境中，免疫接种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张，调节肿瘤宿主环境， 可能是诱导有效抗肿瘤免疫的关键。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鉴定的手段 使用牛痘病毒重组体进行操纵的靶点：“肿瘤微环境作为‘工厂’” 全身无反应性”; 2.评价肿瘤-DLN中抗原呈递的局部调节 用于增强抗肿瘤应答的隔室; 3.评价Treg和效应子的局部调节 使用基于受体和基于抗体的基因融合分子作为疫苗的替代物的功能;和4. 使用抗体和小分子评价肿瘤诱导的调节机制的系统调节 作为疫苗的替代品。

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.