IMMUNOGENE THERAPY FOR ORAL CANCER

该项目的长期目标是开发创新的 用于治疗人类口腔癌晚期形式的治疗模式 癌的 口腔癌是一个主要的健康问题，不仅是因为 与疾病相关的显著死亡率，但也 由于功能缺陷和毁容往往与 与它的治疗。 早期肿瘤通常可以通过 然而，手术和放疗，成功的治疗是相反的， 与治疗时的疾病程度成比例。 不幸的是，诊断往往被推迟，直到肿瘤是在一个较晚的 早期病变通常不显示症状。 的口腔癌 在1986-1991年之间诊断出的，52%处于晚期， 这些病例的五年存活率在白人中为55%， 33%是黑人。 这些惨淡的统计数据证明， 用于治疗晚期头颈部肿瘤的实验。 一 一种特别有前途的方法是刺激宿主的免疫系统， 系统来识别和破坏肿瘤细胞。 有强有力的证据 口腔癌可以被免疫系统检测到， 据报道，在大多数检查的肿瘤中， 约会 T淋巴细胞的存在与 在动物模型和人类的早期研究中预后良好 活组织检查使用免疫刺激剂治疗肿瘤的可能性 细胞因子疗法开始被接受。 IL-2是其中之一 外源性给药治疗癌症的主要候选药物 IL-2刺激浸润性T细胞的活化和增殖， 淋巴细胞 IFN-γ的施用导致了 以及使肿瘤对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。 给予一定剂量的细胞因子。 因为口腔癌很容易 我们建议将IL-2和IFN-γ的基因导入 肿瘤细胞，在那里它们将使用非复制型 腺病毒载体 我们希望能产生高浓度的IL-2， IFN-γ在肿瘤的微环境中并刺激抗肿瘤细胞的生长。 肿瘤免疫反应。 虽然细胞因子的水平会很高， 微观环境，系统水平将保持较低，以避免 与高外源性细胞因子剂量相关的毒性问题。 我们 将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 口腔癌的模型。

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.