IMMUNOGENE THERAPY FOR ORAL CANCER

口腔癌的免疫原治疗

• 批准号: 2872162
• 负责人: NO-HEE PARK
• 金额: $ 3.68万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-02-01 至 2001-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2872162
• 关键词: Adenoviridae; animal genetic material tag; gene therapy; interferon gamma; interleukin 2; laboratory mouse; mouth neoplasms; neoplastic growth; nonhuman therapy evaluation; nucleic acid sequence; tissue /cell culture; transfection /expression vector

The long-term objective of this project is to develop innovative therapeutic modes for the treatment of advanced forms of human oral cancers. Oral cancer is a major health problem not only because of the significant mortality rates associated with the disease, but also because of the functional defects and disfigurement often associated with its treatment. Early stage tumors can usually be managed through surgery and radiotherapy, however, successful treatment is inversely proportional to the extent of the disease at the time of treatment. Unfortunately, diagnosis is often delayed until the tumor is in a later stage as early lesions frequently do not show symptoms. Of oral cancers diagnosed between 1986-1991, 52 percent were at an advanced stage and the five-year survival rate of these cases was 55 percent among whites and 33 percent among blacks. These bleak statistics warrant extensive experimentation for treating advanced head and neck tumors. A particularly promising approach involves stimulating the host's immune system to identify and destroy tumor cells. There is strong evidence that oral cancers can be detected by the immune system, as infiltrating lymphocytes have been reported in the majority of tumors examined to date. The presence of T-lymphocytes has been associated with a favorable prognosis in early studies of animal models and human biopsies. The possibility of treating tumors using immunostimulatory cytokine therapy is beginning to gain acceptance. IL-2 is one of the leading candidates for therapy of cancers as exogenously administered IL-2 stimulates the activation and proliferation of infiltrating T- lymphocytes. Administration of IFN-gamma, has resulted in the reduction of tumors as well as rendering tumors more susceptible to IL-2 immunotherapy, possibly by up regulating MHC I/II or co-stimulatory molecules (B7-1), resulting in effective tumor-antigen presentation to T lymphocytes. Toxic effects, however, are a major problem when high doses of cytokines are administered. Since oral cancers are easily accessible, we propose to deliver the genes for IL-2 and IFN-gamma into the tumor cells where they will be expressed using non-replicating adenovirus vectors. We hope to produce high concentrations of IL-2 and IFN-gamma within the micro-environment of the tumor and stimulate anti- tumor immune responses. Although levels of cytokines will be high in the micro-environment, the systemic levels will remain low to avoid the toxicity problems associated with high exogenous cytokine dosage. We will test the usefulness of cancer gene therapy using non-replicating adenovirus vectors expressing immunostimulatory cytokines in a mouse model of oral cancers.

该项目的长期目标是开发创新型 治疗人类口腔晚期形式的治疗模式 癌症。 口腔癌是一个主要的健康问题，不仅因为 与该疾病相关的显着死亡率，而且 因为经常伴随的功能缺陷和毁容 及其治疗。 早期肿瘤通常可以通过 然而，手术和放射治疗成功的治疗效果却相反 与治疗时疾病的程度成正比。 不幸的是，诊断常常被推迟，直到肿瘤处于后期状态。 早期病变通常不表现出症状。 口腔癌 1986 年至 1991 年间诊断的患者中，52% 已处于晚期阶段 白人中这些病例的五年生存率为 55% 黑人中这一比例为 33%。 这些惨淡的统计数据值得广泛关注 治疗晚期头颈肿瘤的实验。 一个 特别有前途的方法涉及刺激宿主的免疫 识别和破坏肿瘤细胞的系统。 有强有力的证据 口腔癌可以被免疫系统检测到，如浸润性癌 据报道，大多数检查的肿瘤中都有淋巴细胞 日期。 T 淋巴细胞的存在与 动物模型和人类的早期研究中预后良好 活检。使用免疫刺激治疗肿瘤的可能性 细胞因子疗法开始获得认可。 IL-2 是其中之一 外源性癌症治疗的主要候选者 IL-2 刺激浸润性 T-细胞的激活和增殖 淋巴细胞。 施用 IFN-γ，导致了 肿瘤并使肿瘤对 IL-2 更敏感 免疫疗法，可能通过上调 MHC I/II 或共刺激 分子（B7-1），导致有效的肿瘤抗原呈递给 T淋巴细胞。 然而，当高浓度时，毒性作用是一个主要问题。 施用一定剂量的细胞因子。 由于口腔癌很容易 我们建议将 IL-2 和 IFN-gamma 的基因传递到 肿瘤细胞将使用非复制表达 腺病毒载体。 我们希望生产高浓度的 IL-2 和 肿瘤微环境中的 IFN-γ 并刺激抗 肿瘤免疫反应。 尽管细胞因子水平会很高 在微观环境中，系统水平将保持在较低水平，以避免 与高外源细胞因子剂量相关的毒性问题。 我们 将使用非复制测试癌症基因治疗的有效性 在小鼠中表达免疫刺激细胞因子的腺病毒载体 口腔癌模型。