REGULATION OF ANTI-TUMOR IMMUNITY

抗肿瘤免疫的调节

• 批准号: 8058779
• 负责人: ECKHARD R PODACK
• 金额: $ 116.12万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-20 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8058779
• 关键词: REGULATION; ANTI; TUMOR; IMMUNITY

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.

描述（由申请人提供）：有关“肿瘤免疫调节”计划，将微生物学和免疫学系，医学系的血液学和肿瘤学系和病理学系汇总，以解决将免疫疗法带到可以为患者护理和治疗做出重要贡献的紧迫问题。 该计划的远程目标是通过抗肿瘤疫苗的形式找到治疗肿瘤的方法。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力的参数，并允许在长时间内维持抗肿瘤效应的功能。随着时间的流逝，保持抗肿瘤效应子的反应需要我们对记忆形成和维护的理解。该程序在几个项目中的一个重要目标是阐明能够在存在已建立肿瘤的情况下产生和维持记忆的分子机制。抗肿瘤免疫需要Th1免疫反应极化。 在TH2和TH1极化是相互拮抗的范围内，我们建议消除Th2反应可能对抗肿瘤治疗有益。 B细胞是Th2极化的最终效应子，我们已经表明它们的消除允许抗肿瘤活性增加。 因此，在几个项目中检查的程序的第二个目标是分析在没有B细胞的情况下抗肿瘤免疫机制。 这些研究还针对发现分子途径的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支持以下假设：先天免疫反应的激活对于产生强大的适应性反应和记忆产生至关重要。 因此，该计划在三个项目中追求的第三个目标是分析NK细胞和直流对抗肿瘤免疫力的贡献。 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CD8 CTL这种激活方式将在所有项目中研究，并在记忆形成，自体骨髓移植中的免疫力及其在B细胞耗竭条件下的作用中进行检查。 最后，将使用基于热休克蛋白的疫苗来检验以下假设：非免疫原性肿瘤是基于疫苗的免疫疗法的最佳靶标。 I/II期试验 非小细胞肺癌患者将检查免疫反应和临床益处的产生。