TRANSPORT OF PEPTIDES TO EPIDERMAL LANGERHANS CELLS

限制疫苗效力的主要因素是未能靶向关键的抗原呈递细胞。 目前将疫苗靶向树突状细胞的努力使用个体化的离体程序，其对于广泛使用来说过于昂贵。 我们的目标是开发一种具有成本效益的局部方法，将抗原肽递送至表皮朗格汉斯细胞。 将抗原局部递送至表皮朗格汉斯细胞并伴随朗格汉斯细胞迁移的诱导是免疫的有效诱导剂。 我们已经确定了两种潜在的手段，主动透皮转运的肿瘤相关肽。 在这个I期计划中，我们计划1）开发用于将原型鼠肿瘤相关抗原肽转运至朗格汉斯细胞的定量测定。 使用这些测定，我们将2）确定肽经皮转运至表皮朗格汉斯细胞的最有效程序。 如果与已经迁移到引流淋巴结的朗格汉斯细胞相关的肽的量在激活原代T细胞所需的范围内，我们将建立这种方法用于肿瘤免疫治疗的可行性。拟议的商业应用：美国每年诊断出近150万例新的癌症病例;几乎所有这些患者都是“有效肿瘤免疫疗法”的候选人。目前正在鉴定肿瘤相关抗原肽，但需要更好的肽疫苗递送系统。我们建议开发一种利用表皮朗格汉斯细胞的局部肽递送系统，该系统简单且具有成本效益。

A major factor limiting the efficacy of vaccines is the failure to target the critical antigen-presenting cells. Current efforts to target vaccines to dendritic cells use individualized ex vivo procedures that are too costly for widespread use. Our goal is to develop a cost-effective, topical method to deliver antigenic peptides to epidermal Langerhans cells. Topical delivery of antigen to epidermal Langerhans cells with concomitant induction of Langerhans cell migration is a potent inducer of immunity. We have identified two potential means for active transdermal transport of tumor- associated peptides. In this Phase I proposal, we plan to 1) develop quantitative assays for transport of a prototypic murine tumor-associated antigenic peptide to Langerhans cells. Using' these assays, we will 2) determine the most efficient procedure for transdermal transport of peptide to epidermal Langerhans cells. If the amount' of peptide associated with Langerhans cells that have migrated to the draining lymph node is within the range need to activate primary T cells, we will have established the feasibility of this approach for tumor immunotherapy. PROPOSED COMMERCIAL APPLICATIONS: Nearly 1.5 million new cases of cancer are diagnosed in the U.S. annually; virtually all of these patients are candidates for an 'effective tumor immunotherapy. Tumor-associated antigenic peptides are currently being identified, but there is a need for better peptide vaccine delivery systems. We propose to develop a topical peptide delivery system exploiting epidermal Langerhans cells that would be simple and cost-effective.