IMMUNE SUPPRESSION AND IMMUNE ESCAPE IN TUMOR MODELS

描述(改编自《调查者摘要》)：近年来 研究人员已经研究了免疫反应并开发了疫苗。 对抗病毒诱导的肿瘤。尤其是人乳头瘤病毒16型 与宫颈癌相关的问题一直是人们关注的焦点。按顺序 为了设计一种基于多肽的人类使用的治疗性疫苗，他们有 建立了两种重要的小鼠肿瘤模型，即人乳头瘤病毒型 16加激活的ras诱导肿瘤和人腺病毒加激活的ras 诱发肿瘤。尽管在预防肿瘤生长方面取得了成功，但 在这些肿瘤模型中，疫苗接种只取得了非常有限的成功 这些疫苗的治疗用途。像免疫抑制这样的几个障碍 而这些肿瘤模型中的免疫逃逸会或可能会阻碍 治疗效果。这些潜在的障碍是：1)激活的ras诱导 免疫抑制和免疫逃逸，2)局部辐射或某些 化疗导致免疫抑制，令人惊讶的是，疫苗导致 免疫抑制。为了描述和克服这些障碍， 它们将解决以下目标：1)分析和制定 拮抗活化ras诱导的免疫抑制和免疫的方法 逃逸，2)临床相关局部放射的影响分析 以及某些化疗药物对治疗性疫苗在这些地区的效力 病毒诱导的衰老小鼠肿瘤模型及3)分析与发展 方法对抗多肽疫苗诱导的免疫抑制。至 为实现这些目标，将使用以下方法：1)中和 活化的ras癌基因诱导的TGFb，1b)阻断激活的ras 法尼基蛋白转移酶抑制剂，以及1c)定义一般 激活ras的抗原处理阻断效应，以及1D)特征 在激活的ras表达细胞中诱导的其他免疫逃逸机制。2) 测量局部照射或某些化疗对患者的影响 治疗性疫苗在衰老小鼠中诱导T细胞反应的效力。 3a)多肽经常引起的免疫抑制的特征 通过分析疫苗的药代动力学，为肿瘤疫苗奠定基础 成分和，3b)转化免疫抑制多肽为基础的癌症 通过替代递送系统将疫苗转化为免疫疫苗。这 联合分析将有助于阐明免疫抑制和免疫 病毒诱导的肿瘤模型中的逃逸机制及其治疗途径 对抗他们。这种机制也可以在其他方面发挥作用 临床上，相关肿瘤。因此，结果可能会直接 对正在进行的和未来的治疗的设计和执行的影响 癌症疫苗试验。

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.