DNA-based Vaccine for Treatment of Oral Carcinoma

描述：口腔癌疫苗的研制是本实验室目前的主要研究目标。长期目标是开发一种可用于头颈部鳞状细胞癌(SCCHN)患者的整体管理的疫苗。疫苗接种策略结合了产生强大的抗肿瘤免疫反应的已知要求--抗原呈递、同种异体刺激和免疫增强细胞因子的分泌。该疫苗是通过将DNA从鳞癌细胞转移到高度免疫原性的同基因/异基因细胞系来制备的，在该细胞系中表达了肿瘤相关抗原(TAA)的基因。受体细胞在DNA转移之前被修饰以分泌细胞因子。这种疫苗的原理是，TAA是癌细胞中突变和失调基因的产物，将肿瘤DNA转移到受体细胞中会导致TAA特异性基因的稳定整合和长期表达。先前在小鼠身上发表的数据表明，用转基因细胞免疫可以诱导强烈的抗肿瘤免疫反应，免疫记忆和延长生存时间。我们最近的研究(PNAS，99：9415-9420,2002)证实了口腔癌DNA转基因受体细胞的免疫原性。这种类型的疫苗有许多优点，包括选择免疫原性受体细胞，在其中复制转移的DNA。因此，可以用从少量肿瘤组织中提取的DNA来制备疫苗。现在需要对口腔癌小鼠模型进行进一步研究，以确定疫苗免疫治疗效果的机制，并优化这一有希望的策略。利用从鳞癌中导入DNA的小鼠抗原提呈细胞，将确定制备有效疫苗所需的最小肿瘤组织数量和介导肿瘤排斥反应的细胞类型。表达TAAs的细胞将在转基因细胞群中得到丰富，从而增加疫苗的治疗潜力。将评估其可能的毒性影响。这些研究将为肿瘤排斥反应的机制和疫苗接种策略的优化提供指导。预计，单独使用或与传统疗法结合使用的有效疫苗的开发将扩大口腔癌患者未来的治疗选择。

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.