IMMUNOTHERAPY BY IN VIVO GENE TRANSFER INTO TUMORS

通过体内基因转移到肿瘤中进行免疫治疗

基本信息

批准号：
6269612
负责人：
Gary J Nabel
金额：
$ 28.32万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-04-17 至 1999-03-31
项目状态：
已结题

项目摘要

Strategies to enhance tumor regression by stimulating the immune response to malignant cells have shown limited efficacy in animal and human studies, but represent an important potential approach to the treatment of cancer. We have developed a gene transfer approach to the immunotherapy of malignancy by expression of cell surface antigens in tumors using direct gene transfer in vivo. We had previously shown that direct transfer of recombinant genes to tumors in vivo alters their immunogenicity. Preclinical studies had shown that introduction of a gene encoding a highly immunogenic protein, from an allogeneic class I major histocompatibility complex (MHC) gene, in transplantable mouse tumors induced specific cytolytic T cells against this protein and also elicited a response against unmodified tumor cells, causing tumor regression or cure in animals. Human studies of direct gene transfer with foreign MHC have also been performed with the support of this grant and applied to melanoma in tow independent human phase I clinical studies completed at The University of Michigan medical Center with encouraging preliminary results. In this proposal, delivery of a foreign histocompatibility gene directly into colon carcinoma metastatic to liver will be optimized, and gene expression and immune response in patients will be analyzed to understand the mechanisms which lead to successful responses. Expression of allogeneic MHC will be assessed, and the immunologic basis of antitumor responses. Expression of allogeneic MHC will be assessed, and the immunologic basis of antitumor responses will be characterized. Such analyses will also be used to develop systems which allow molecular cloning of immunologically relevant tumor- associated antigens in the future. Finally, we will develop modifications of the current protocol which will improve its efficacy in humans. To understand and improve upon this gene transfer strategy, we will: 1) perform catheter delivery of a foreign MHC gene, HLA- B7, into metastatic liver lesions of colon cancer utilizing improved vectors and liposomes, 2) analyze gene expression, define correlates of successful immune responses and delineate mechanisms of tumor rejection, and 3) develop novel gene transfer approaches using combination gene therapy of foreign MHC and the p21 cyclin- dependent kinase, which arrests cell proliferation and induces terminal differentiation which may promote further changes which induce immune recognition of tumors. These studies expand on the present technology of current human clinical trials to improve the efficacy of gene transfer approaches to cancer and will provide insight into the molecular basis of immune recognition in malignancy.

通过刺激免疫增强肿瘤消退的策略对恶性细胞的反应在动物和动物中显示出有限的功效人类研究，但代表了一种重要的潜在方法癌症的治疗。我们开发了一种基因转移方法通过细胞表面表达进行恶性肿瘤的免疫治疗使用体内直接基因转移来识别肿瘤中的抗原。我们有先前表明，将重组基因直接转移至肿瘤体内改变其免疫原性。临床前研究表明引入编码高免疫原性蛋白质的基因，同种异体 I 类主要组织相容性复合体 (MHC) 基因，可移植小鼠肿瘤诱导特异性溶细胞 T 细胞这种蛋白质也引发了针对未修饰肿瘤的反应细胞，导致动物肿瘤消退或治愈。人类研究还进行了与外源 MHC 的直接基因转移这笔赠款的支持并应用于两个独立的黑色素瘤人类 I 期临床研究在英国大学完成密歇根医疗中心取得了令人鼓舞的初步结果。在这个建议，将外源组织相容性基因直接传递到结肠癌肝转移将得到优化，基因将分析患者的表达和免疫反应了解导致成功应对的机制。将评估同种异体 MHC 的表达，并评估免疫学抗肿瘤反应的基础。同种异体 MHC 的表达将是评估，抗肿瘤反应的免疫学基础将是特点。此类分析也将用于开发系统允许免疫相关肿瘤的分子克隆未来的相关抗原。最后我们将开发对现行方案的修改将提高其功效人类。为了理解和改进这种基因转移策略，我们将： 1) 进行外源 MHC 基因 HLA- 的导管输送 B7、结肠癌转移性肝病灶利用改善载体和脂质体，2) 分析基因表达，定义相关性成功的免疫反应和描述肿瘤的机制排斥，以及3）开发新的基因转移方法国外MHC与p21细胞周期蛋白联合基因治疗依赖性激酶，可阻止细胞增殖并诱导终末期分化可能会促进进一步的变化，从而诱发肿瘤的免疫识别。这些研究扩展了目前目前的人体临床试验技术可提高疗效基因转移方法治疗癌症，并将提供对癌症的深入了解恶性肿瘤免疫识别的分子基础。