DNA-based Vaccine for Treatment of Oral Carcinoma

用于治疗口腔癌的 DNA 疫苗

• 批准号: 6773914
• 负责人: EDWARD P. COHEN
• 金额: $ 27.28万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-15 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6773914
• 关键词: DNA; antigen presenting cell; cytotoxic T lymphocyte; dendritic cells; disease /disorder model; enzyme linked immunosorbent assay; fibroblasts; head /neck neoplasm; laboratory mouse; mouth neoplasms; neoplasm /cancer immunotherapy; nonhuman therapy evaluation; oral health; squamous cell carcinoma; transfection; tumor antigens; vector vaccine

DESCRIPTION: Vaccine development for oral carcinoma is the current major research objective of my laboratory. The long-term objective is to develop a vaccine that can be used in the overall management of patients with squamous cell carcinoma of the head and neck (SCCHN). The vaccination strategy combines known requirements for generation of a robust anti tumor immune response--antigen presentation, allogeneic stimulation and the secretion of immune-augmenting cytokines. The vaccine is prepared by transfer of DNA from squamous carcinoma cells into a highly immunogenic syngeneic/allogeneic cell line in which genes specifying tumor associated antigens (TAAs) are expressed. The recipient cells are modified in advance of DNA-transfer to secrete cytokines. This type of vaccine is based on the principle that TAAs are the products of mutant and dysregulated genes in cancer cells and that transfer of tumor-DNA into recipient cells results in stable integration and long-term expression of the genes specifying TAAs. Prior published data in mice indicate that immunization with transfected cells induced strong anti tumor immune responses, immunological memory and prolongation of survival. Our recent studies (PNAS, 99: 9415-9420, 2002) confirm the immunogenic properties of recipient cells transfected with DNA from human oral carcinomas. This type of vaccine has a number of advantages, including the selection of immunogenic recipient cells, in which the transferred DNA is replicated. Thus, the vaccine can be prepared with DNA derived from small amounts of tumor tissue. Further studies in a mouse model of oral carcinoma are now required to define the mechanisms of the immunotherapeutic effects of the vaccine and to optimize this promising strategy. Using murine antigen presenting cells transfected with DNA from squamous carcinomas, the minimum amount of tumor tissue required to prepare an effective vaccine and the cell types mediating tumor rejection will be determined. The transfected cell-population will be enriched for cells that express TAAs, to increase the therapeutic potential of the vaccine. Its possible toxic effects will be evaluated. These studies will provide insights into the mechanism of tumor rejection and guidelines for optimization of the vaccination strategy. It is expected that development of an effective vaccine to be used alone or in combination with conventional therapy will expand the future therapeutic options available for patients with oral cancer.

描述：口服癌的疫苗开发是我实验室目前的主要研究目标。长期目标是开发可用于头颈部鳞状细胞癌（SCCHN）患者的总体治疗中的疫苗。疫苗接种策略结合了生成强大抗肿瘤免疫反应的已知要求 - 抗原表现，同种异体刺激和免疫增强细胞因子的分泌。通过将DNA从鳞状癌细胞转移到高度免疫原性/同种异体细胞系中，制备该疫苗，其中表达了指定肿瘤相关抗原（TAA）的基因。在DNA转移之前，对受体细胞进行了修饰，以分泌细胞因子。这种类型的疫苗基于这样的原理：TAA是癌细胞中突变和失调基因的产物，并且将肿瘤-DNA转移到受体细胞中会导致稳定的整合和指定TAA的基因的长期表达。事先在小鼠中发表的数据表明，转染的细胞免疫会诱导强抗肿瘤免疫反应，免疫记忆和生存的延长。我们最近的研究（PNAS，99：9415-9420，2002）证实了从人口腔癌转染DNA的受体细胞的免疫原性。这种类型的疫苗具有许多优点，包括选择免疫原性的受体细胞，其中复制了转移的DNA。因此，可以用少量肿瘤组织衍生的DNA制备疫苗。现在需要在口服癌的小鼠模型中进行进一步的研究，以定义疫苗的免疫治疗作用的机制，并优化这种有前途的策略。使用从鳞状癌转染DNA的鼠抗原细胞，将确定制备有效疫苗所需的最小肿瘤组织量和介导肿瘤排斥的细胞类型所需的肿瘤组织。转染的细胞构造将富含表达TAA的细胞，以增加疫苗的治疗潜力。将评估其可能的毒性作用。这些研究将提供有关肿瘤排斥机制和优化疫苗接种策略的指南的见解。可以预期，开发有效的疫苗可以单独使用或与常规疗法结合使用，将扩大针对口腔癌患者可用的未来治疗选择。