DEVELOPMENT OF IMMUNOTHERAPIES FOR CHRONIC MYELOID LEUKEMIA

目前，慢性粒细胞白血病的治愈性治疗主要局限于小 符合HLA-1的稳定期疾病患者比例 匹配的骨髓移植 最近人们又对 在癌症免疫疗法的开发上， 基础免疫学 这些发现包括了 了解抗原呈递，T细胞调节， 耐受性或无反应性的机制。 理论上，许多癌症都有可能 显性癌基因突变形式的肿瘤抗原，病毒 癌基因或其他新抗原。 CML是一个例子，其中p210 BCR/ABL 癌基因本身是一种可能的肿瘤抗原， 原癌基因，如p53和p21 ras，通常在 疾病的晚期形式。 很明显，大多数或所有患者 慢性粒细胞白血病患者对肿瘤没有免疫反应， 免疫反应 对白血病细胞的免疫反应可能受损 因为白血病抗原通常以这种方式呈递给T细胞， 方式，以迫使宽容的发展，而不是积极的 免疫力 耐受性被认为是由以下因素引起的： 在不存在通过CD 28的共刺激信号的情况下，将抗原结合至T细胞。 该项目的目标是开发动物模型，以探索 对白血病抗原（p210 BCR/ABL）的免疫应答，以研究 操纵体内免疫应答作为体外研究的相关性 与其他项目中进行的人类细胞，以寻找新的方法来诱导 白血病动物的有效免疫反应， 临床试验，并产生新的CML动物模型， 准确反映人类疾病。 这个项目生产的模型 也将被其他项目的研究人员用来测试新的概念 关于耐受性或改变肿瘤免疫反应的技术。 从长远来看，该项目应有助于发展 用于人类白血病和淋巴瘤的新疗法。

At present, curative therapy for CML is limited primarily to the small fraction of patients with stable phase disease who are eligible for an HLA- matched bone marrow transplant. There has recently been renewed interest in developing immunotherapies for cancer because of a number of discoveries in basic immunology. These discoveries include major advances in the understanding of antigen presentation, T cell regulation, and the mechanisms of tolerance or anergy. In theory, many cancers have potential tumor antigens in the form of mutations in dominant oncogenes, viral oncogenes, or other neoantigens. CML is an example, where the p210 BCR/ABL oncogene itself is a possible tumor antigen, as are mutations in other proto-oncogenes such as p53 and p21 ras which are commonly observed in advanced forms of the disease. It is evident that most or all patients with CML generate either no immune response to athe tumor or an ineffective immune response. The immune response to leukemia cells may be impaired because leukemic antigens are typically presented to T cells in such a manner as to force the development of tolerance rather than active immunity. Tolerance is believed to be caused by the presentation of antigen to T cells in the absence of a costimulatory signal through CD28. The goals of this project will be to develop animal models to explore the immune response to a leukemia antigen (p210BCR/ABL), to investigate ways of manipulating the immune response in vivo as a correlate to in vitro studies with human cells conducted in other projects, to find novel ways to induce an effective immune response in leukemic animal which could lead to clinical trials, and to generate new animal models of CML which more accurately reflect human disease. This models produced by this project will also be used by investigators in other projects to test new concepts about tolerance or techniques for altering immune responses to tumors. Over the long term, this project should contribute tot he development of novel therapies for human leukemias and lymphomas.