CHEMOTHERAPY FOR IMMUNE DESTRUCTION OF EBV TUMORS

EBV 肿瘤免疫破坏的化疗

基本信息

批准号：
2105447
负责人：
RICHARD Frederick AMBINDER
金额：
$ 26.77万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-05-01 至 1999-01-31
项目状态：
已结题

项目摘要

Targeting tumor specific antigens immunologically is an attractive approach to the destruction of tumor cells most refractory to chemo and radiotherapy. Epstein-Barr virus (EBV) malignancies offer some interesting opportunities in this regard. Healthy immunocompetent individuals show an intense cytotoxic memory T cell response to EBV latency antigens. However, the immunodominant viral latency antigens are not expressed in most EBV malignancies. Restricted viral antigen expression in tumors, correlates with methylation of transcriptional regulatory elements of the EBV genome. Treatment of Burkitt's cell lines with a demethylating agent (5-azacitidine) leads to: (i) demethylation of these regulatory elements, (ii) a promoter switch, and (iii) expression of the full panel of EBV latency antigens including those frequently targeted by cytotoxic T cells. A comparable effect of this or other pharmacologic agents that alter patterns of viral gene transcription in tumors in vivo might facilitate immune destruction of EBV(+) tumors. In this proposal we are seeking support for the study of this approach to the treatment of EBV(+) malignancies with restricted patterns of antigen expression. We will study patients without history of HIV infection or history of organ transplantation. We will begin by assaying tumors at high risk for EBV-association (Hodgkin's disease, nasopharyngeal carcinoma, undifferentiated gastric cancer) for the presence of EBV in tumor cells. Patients with these tumors will be studied to characterize their conventional therapies will be eligible for enrollment in a trial to determine the effect of pharmacologic manipulation on patterns of viral gene expression in tumor tissue, and/or determining antitumor therapeutic efficacy of such agent. The trials will be conducted under the auspices of the John Hopkins Oncology Center Drug Development Program and will utilize the clinical resources of the General Clinical Research Inpatient and Outpatient Centers. In an initial trial, 5-azacitidine, will be administered to patients with biopsy-accessible disease by 7-day continuous infusion. Patients will undergo biopsy before and after treatment; and tumor tissue will be assayed for patterns of methylation, transcription and antigen expression. This will be followed by the investigation of other agents that may alter patterns of viral gene expression. This will be followed by the investigation of other agents that may alter patterns of viral gene expression including other demethylating agents such as 5-aza- 2'deoxycytidine and phenylbutyrate. Ultimately, such drugs might be used in place of conventional therapy, as "consolidation" following conventional therapy, or in combination with adoptive cellular immunotherapy to facilitate immune-mediated destruction of residual tumor cells.

在免疫学上靶向肿瘤特异性抗原是一种有吸引力的破坏肿瘤细胞最难治性的方法和放疗。爱泼斯坦 - 巴尔病毒（EBV）恶性肿瘤提供了一些在这方面有趣的机会。健康的免疫能力个体显示出强烈的细胞毒性记忆T细胞对EBV的反应潜伏期抗原。但是，免疫主导病毒潜伏抗原是在大多数EBV恶性肿瘤中没有表达。受限病毒抗原在肿瘤中的表达，与转录的甲基化相关 EBV基因组的调节元素。伯基特细胞系的处理脱甲基剂（5-氮杂丁）导致：（i）脱甲基化在这些调节元素中，（ii）启动子开关和（iii） EBV潜伏期抗原的完整面板的表达包括通常由细胞毒性T细胞靶向。可比的效果或其他改变病毒基因模式的药理学剂体内肿瘤的转录可能有助于免疫破坏 EBV（+）肿瘤。在此提案中，我们正在寻求研究这种方法治疗EBV（+）恶性肿瘤的情况有限抗原表达。我们将研究没有艾滋病毒病史的患者器官移植的感染或病史。我们将从测定EBV缔合高风险的肿瘤（霍奇金氏病，鼻咽癌，未分化的胃癌） EBV在肿瘤细胞中的存在。这些肿瘤的患者将是被研究以表征其常规疗法将有资格在试验中注册以确定药理学的影响操纵肿瘤组织中病毒基因表达模式和/或确定该药物的抗肿瘤治疗功效。试验将在约翰·霍普金斯肿瘤学中心的主持下进行药物开发计划，并将利用一般临床研究住院和门诊中心。在初步试验（5-齐丁丁）将针对患者进行 7天连续输注可通过活检可进入的疾病。患者会治疗前后进行活检；和肿瘤组织将是分析甲基化，转录和抗原的模式表达。随后将对其他代理进行调查这可能会改变病毒基因表达的模式。这将遵循通过研究其他可能改变病毒模式的药物基因表达包括其他脱甲基剂，例如5-aza- 2'DeoxyCytidine和苯基丁酸。最终，可以使用此类药物代替常规疗法，作为“合并”以下常规疗法，或与收养细胞结合免疫疗法以促进免疫介导的残留肿瘤破坏细胞。