REGULATION OF ANTI-TUMOR IMMUNITY

描述（由申请人提供）：“肿瘤免疫调节”计划汇集了来自微生物学和免疫学系，医学系血液学和肿瘤学系以及病理学系的研究人员，共同致力于将免疫治疗带到一个可以为患者护理和治疗做出重要贡献的点的紧迫问题。 该计划的长期目标是找到以抗肿瘤疫苗形式的免疫疗法帮助治疗肿瘤的方法。为了开发成功的免疫疗法，有必要定义允许产生抗肿瘤免疫并允许在延长的时间段内维持抗肿瘤效应子功能的参数。随着时间的推移维持抗肿瘤效应反应需要我们理解记忆的形成和维持。该计划在几个项目中的一个重要目标是阐明能够在已建立的肿瘤存在下产生和维持记忆的分子机制。抗肿瘤免疫需要免疫应答的TH 1极化。 在一定程度上，TH 2和TH 1极化是相互拮抗的，我们认为，消除TH 2反应可能是有益的抗肿瘤治疗。B细胞是TH 2极化的最终效应子，我们已经证明，它们的消除可以增加抗肿瘤活性。 因此，在几个项目中检查的该计划的第二个目标是在没有B细胞的情况下分析抗肿瘤免疫的机制。 这些研究也旨在发现B细胞抑制抗肿瘤TH 1应答的分子途径。 我们自己的研究和其他人的研究都支持这样一个假设，即先天免疫反应的激活对于产生强大的适应性反应和记忆很重要。 因此，在三个项目中追求的计划的第三个目标是分析NK细胞和DC对抗肿瘤免疫的贡献。 由于我们已经表明肿瘤细胞分泌的热休克蛋白激活DC、NK和CD 8 CTL，因此将在所有项目中研究这种激活模式，并就记忆形成、自体骨髓移植中免疫力的产生及其在B细胞耗竭条件下的作用进行检查。 最后，将使用基于热休克蛋白的疫苗来检验非免疫原性肿瘤是基于疫苗的免疫疗法的最佳靶点的假设。 I/II期试验， 非小细胞肺癌患者将检查免疫应答的产生和临床益处。

DESCRIPTION (provided by applicant): The Program on "Regulation of Tumor Immunity" brings together investigators from the Department of Microbiology and Immunology, the Division of Hematology and Oncology in the Department of Medicine and the Department of Pathology to work together on the pressing problem of bringing Immunotherapy to a point where it can make an important contribution to patient care and treatment. The long-range goal of the program is to find ways to treat tumors with the aid of immunotherapy in the form of anti tumor vaccines. In order to develop successful immunotherapy it is necessary to define the parameters that allow the generation of anti tumor immunity and allow the maintenance of anti tumor effector functions over prolonged periods of time. Maintaining anti tumor effector responses over time necessitates our understanding of memory formation and maintenance. One important goal of the program in several projects is the elucidation of molecular mechanisms able to generate and maintain memory in the presence of established tumors. Anti tumor immunity requires TH1 polarization of the immune response. To the extent that TH2 and TH1 polarization are mutually antagonistic we suggest that elimination of TH2 responses may be beneficial for anti tumor therapy. B cells are the final effectors of TH2 polarization and we have shown that their elimination allows increased anti tumor activity. A second goal of the program examined in several projects therefore is the analysis of the mechanisms of anti tumor immunity in the absence of B cells. These studies are also aimed at the discovery of molecular pathways by which B cells dampen the anti tumor TH1 response. Our own studies and those by others support the hypothesis that the activation of the innate immune response is important for the generation of a powerful adaptive response and the generation of memory. The third goal of the program pursued in three projects therefore is the analysis of the contribution of NK cells and DC to anti tumor immunity. Since we have shown that heat shock proteins secreted by tumor cells activate DC, NK and CD8 CTL this mode of activation will be studied in all projects and examined with regard to memory formation, generation of immunity in autologous bone marrow transplantation and in its effects under conditions of B cell depletion. Finally, a heat shock protein based vaccine will be used to test the hypothesis that non-immunogenic tumors are the best targets for vaccine-based immunotherapy. A phase I/II trial for non-small cell lung carcinoma patients will examine generation of an immune response and clinical benefit.