IMMUNOGENE THERAPY FOR ORAL CANCER

该项目的长期目标是开发创新的 晚期人类口腔癌的治疗模式 癌症。口腔癌是一个主要的健康问题，不仅是因为 与这种疾病相关的显著死亡率，但也 因为功能缺陷和毁容经常伴随着 以及它的治疗方法。早期肿瘤通常可以通过 然而，手术和放射治疗的成功恰恰相反。 与治疗时的疾病程度成正比。 不幸的是，诊断往往被推迟到肿瘤出现的较晚阶段。 早期皮损通常没有症状。口腔癌 在1986-1991年间确诊的52%的患者处于晚期， 这些病例的五年存活率在白人中为55%。 在黑人中的比例为33%。这些惨淡的统计数字值得广泛研究。 治疗晚期头颈部肿瘤的实验。一个 特别有希望的方法包括刺激宿主的免疫力 识别和摧毁肿瘤细胞的系统。有强有力的证据表明 口腔癌可以被免疫系统检测为浸润性的 据报道，在大多数接受检查的肿瘤中，淋巴细胞 约会。T淋巴细胞的存在与一种 动物模型和人类早期研究的良好预后 活组织检查。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是其中一种 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。给予干扰素-伽马，已导致减少 以及使肿瘤更容易受到IL-2的影响 免疫治疗，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递呈给 T淋巴细胞。然而，当毒物浓度过高时，毒性效应是一个主要问题。 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和干扰素-γ的基因转移到 使用非复制方式表达它们的肿瘤细胞 腺病毒载体。我们希望产生高浓度的IL-2和 干扰素-γ在肿瘤的微环境中并刺激抗- 肿瘤免疫反应。尽管细胞因子水平将在 在微观环境方面，系统水平将保持较低水平，以避免 与高外源性细胞因子剂量相关的毒性问题。我们 将使用非复制技术测试癌症基因治疗的有效性 表达免疫刺激细胞因子的腺病毒载体在小鼠中的表达 口腔癌模型。

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.