IMMUNE SUPPRESSION AND IMMUNE ESCAPE IN TUMOR MODELS

肿瘤模型中的免疫抑制和免疫逃逸

• 批准号: 2670924
• 负责人: WIJBE MARTIN KAST
• 金额: $ 22.96万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-05 至 2002-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2670924
• 关键词: aging; alkyltransferase; antigen presentation; cervix neoplasms; disease /disorder model; enzyme inhibitors; human papillomavirus; immunosuppression; laboratory mouse; neoplasm /cancer chemotherapy; neoplasm /cancer immunology; neoplasm /cancer radiation therapy; neoplasm /cancer vaccine; oncogenes; pharmacokinetics; synthetic tumor antigen; synthetic vaccines; transforming growth factors; vaccine development; virus related neoplasm /cancer

DESCRIPTION (Adapted from the Investigator's Abstract): In recent years the investigators have studied the immune responses and developed vaccines against virus-induced tumors. Especially human papilloma virus type 16 related to cervical cancer has been the focus of their attention. In order to design a peptide based therapeutic vaccine for human use, they have developed two important mouse tumor models namely human papilloma virus type 16 plus activated ras induced tumors and human adenovirus plus activated ras induced tumors. Despite successes in prevention of tumor outgrowth through vaccination in these tumor models, only very limited success was obtained in therapeutic use of these vaccines. Several hurdles like immune suppression and immune escape in these tumor models stood or could stand in the way of therapeutic results. These potential hurdles are: 1) Activated ras induced immune suppression and immune escape, 2) Local radiation or certain chemotherapy induced immune suppression and surprisingly, 3) Vaccine induced immune suppression. In order to characterize and overcome these hurdles, they will address the following aims: 1) Analysis and development of methods to antagonize activated ras induced immune suppression and immune escape, 2) Analysis of the effects of clinically relevant local radiation and certain chemotherapies on the potency of therapeutic vaccines in these virus-induced tumor models in aging mice and, 3) Analysis and development of methods to antagonize peptide based vaccine induced immune suppression. To achieve these aims the following methodology will be used: 1a) Neutralizing TGFb induced by the activated ras oncogene, 1b) Blocking activated ras with farnesyl protein transferase inhibitors, as well as 1c) Defining a general antigen processing blocking effect by activated ras, and 1d) Characterizing other immune escape mechanisms induced in activated ras express cells. 2) Measuring the effects of local irradiation or certain chemotherapies on the potency of therapeutic vaccines to induce T cell responses in aging mice. 3A) Characterizing the immune suppression frequently induced by peptide based cancer vaccines through analyzing the pharmacokinetics of the vaccine components and, 3b) Converting immuno-suppressive peptide based cancer vaccines into immunizing vaccines by alternative delivery systems. This combined analysis will shed light on the immune suppression and immune escape mechanisms in the virus induced cancer models and on ways of counteracting them. Such mechanisms could also play a role in other clinically, relevant tumors. Therefore, the results could have direct implications on the design and execution of ongoing and future therapeutic cancer vaccine trials.

描述（改编自研究者摘要）：近年来， 研究人员已经研究了免疫反应并开发了疫苗 对抗病毒诱发的肿瘤。 尤其是人乳头瘤病毒16型 与宫颈癌有关的疾病一直是他们关注的焦点。 为了 为了设计一种基于肽的治疗性疫苗， 开发了两种重要的小鼠肿瘤模型， 16+活化ras诱导的肿瘤和人腺病毒+活化ras 诱发肿瘤。 尽管在预防肿瘤生长方面取得了成功， 在这些肿瘤模型中接种疫苗，仅获得非常有限的成功， 这些疫苗的治疗用途。 几个障碍，如免疫抑制 在这些肿瘤模型中，免疫逃逸阻碍了 治疗效果。 这些潜在的障碍是：1）激活ras诱导 免疫抑制和免疫逃逸，2）局部辐射或某些 化疗诱导的免疫抑制，并且令人惊讶的是，3）疫苗诱导的 免疫抑制 为了描述和克服这些障碍， 他们将致力于以下目标：1）分析和发展 拮抗活化的ras诱导的免疫抑制和免疫抑制的方法 逃逸，2）分析临床相关局部辐射的影响 和某些化疗对治疗性疫苗的效力， 病毒诱导的衰老小鼠肿瘤模型，3）分析和开发 拮抗基于肽的疫苗诱导的免疫抑制的方法。 到 为了实现这些目标，将使用以下方法：1a）中和 1b）用TGFb阻断活化的ras癌基因， 法呢基蛋白转移酶抑制剂，以及1c）定义一种通用的 活化ras的抗原加工阻断作用，和1d）表征 在活化的ras表达细胞中诱导的其它免疫逃逸机制。 （二） 测量局部照射或某些化学疗法对 治疗性疫苗在衰老小鼠中诱导T细胞应答的效力。 3A）表征肽经常诱导的免疫抑制 通过分析疫苗的药代动力学， 3b）转化基于免疫抑制肽的癌症 通过替代的递送系统将疫苗转化为免疫疫苗。 这 联合分析将揭示免疫抑制和免疫 病毒诱导的癌症模型中的逃逸机制以及 抵消他们。 这种机制也可以在其他方面发挥作用。 临床相关肿瘤。 因此，结果可能直接 对正在进行的和未来的治疗设计和执行的影响 癌症疫苗试验