Treatment of Melanoma with Optimzed Peptide Vaccines

描述（由申请人提供）：开发针对癌症的有效治疗性疫苗的主要挑战是克服对肿瘤相关抗原的免疫耐受性。作为耐受的结果，高亲和力的CD8 T淋巴细胞，其是能够识别和杀死肿瘤细胞的效应器，不能被常规疫苗诱导。我们设计了一种新的疫苗接种方法，该方法利用代表CD8 T细胞表位的合成肽、作为有效免疫佐剂的Toll样受体激动剂和免疫共刺激单克隆抗体。使用这种疫苗的小鼠黑色素瘤模型的初步数据，我们称之为TriVax（因为它的3种基本成分），表明这种策略在诱导肿瘤反应性CD8 T细胞方面是有效的，具有治疗效果。在此，我们建议对TriVax进行优化研究，以证明该方法的临床可行性（具体目标1）。我们将进行实验以进一步优化TriVax，旨在开发针对晚期肿瘤的有效疫苗（具体目标2）。最后，我们将通过研究几种潜在的CD8 T细胞表位的应答来验证TriVax免疫策略的使用，以确定高亲合力CD8 T细胞应答的诱导是否与体外肿瘤识别相关，是否与针对已建立的黑素瘤的体内治疗效果相关，以及是否与表位扩散和自身免疫的诱导相关（具体目标3）。我们的目标是，从这些研究中获得的临床前数据将产生足够的热情，将这种方法应用于临床。

DESCRIPTION (provided by applicant): A major challenge for developing effective therapeutic vaccines against cancer is overcoming immunological tolerance to tumor-associated antigens. As the result of tolerance, high avidity CD8 T lymphocytes, which are the effectors capable of recognizing and killing tumor cells are not induced by conventional vaccines. We have designed a novel vaccination approach that utilizes synthetic peptides representing CD8 T cell epitopes, Toll-like receptor agonists that function as a potent immunological adjuvants and immune costimulatory monoclonal antibodies. Preliminary data in a mouse model of melanoma using this vaccine, which we call TriVax (for its 3 basic components) demonstrates that this strategy is effective in inducing tumor-reactive CD8 T cells with therapeutic effectiveness. Here we propose to carry out optimization studies of TriVax to demonstrate the clinical feasibility of this approach (specific aim 1). We will perform experiments to further optimize TriVax with the aim of developing an effective vaccine against advanced tumors (specific aim 2). Lastly, we will validate the use of the TriVax immunization strategy by studying the responses of several potential CD8 T cell epitopes to determine whether the induction of high avidity CD8 T cell responses correlates with in vitro tumor recognition, with in vivo therapeutic effects against established melanomas, and with the induction of epitope spreading and autoimmunity (specific aim 3). Our goal is that the preclinical data derived from these studies will generate sufficient enthusiasm to take this approach into the clinic.