REGULATION OF ANTI-TUMOR IMMUNITY

描述（由申请人提供）：“肿瘤免疫调节”项目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和病理学系的研究人员，共同研究将免疫疗法推向一个可以为患者护理和治疗做出重要贡献的紧迫问题。该项目的长期目标是找到利用抗肿瘤疫苗形式的免疫疗法来治疗肿瘤的方法。为了开发成功的免疫疗法，有必要确定允许产生抗肿瘤免疫并允许长时间维持抗肿瘤效应功能的参数。随着时间的推移，维持抗肿瘤效应反应需要我们对记忆形成和维持的理解。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的情况下产生和维持记忆的分子机制。抗肿瘤免疫需要TH1极化的免疫反应。在一定程度上，TH2和TH1极化是相互拮抗的，我们认为消除TH2反应可能有利于抗肿瘤治疗。B细胞是TH2极化的最终效应器，我们已经证明，消除它们可以增加抗肿瘤活性。因此，在几个项目中研究的第二个目标是分析在缺乏B细胞的情况下抗肿瘤免疫的机制。这些研究也旨在发现B细胞抑制抗肿瘤TH1反应的分子途径。我们自己的研究和其他人的研究都支持这样的假设，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的产生很重要。因此，三个项目所追求的第三个目标是分析NK细胞和DC对抗肿瘤免疫的贡献。由于我们已经证明肿瘤细胞分泌的热休克蛋白激活DC、NK和CD8 CTL，这种激活模式将在所有项目中进行研究，并检查记忆形成、自体骨髓移植中免疫的产生及其在B细胞耗竭条件下的影响。最后，一种基于热休克蛋白的疫苗将用于验证非免疫原性肿瘤是基于疫苗的免疫治疗的最佳靶点的假设。I/II期临床试验

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.