Treatment of Melanoma with Optimzed Peptide Vaccines

描述（由申请人提供）：开发有效的治疗性癌症疫苗的主要挑战是克服对肿瘤相关抗原的免疫耐受。由于具有耐受性，传统疫苗无法诱导具有识别和杀伤肿瘤细胞效应的高活动性CD8 T淋巴细胞。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。在使用这种疫苗的黑色素瘤小鼠模型中的初步数据，我们称之为TriVax（因为它有3个基本成分）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，目的是开发针对晚期肿瘤的有效疫苗（特异性目标2）。最后，我们将通过研究几种潜在CD8 T细胞表位的反应来验证TriVax免疫策略的使用，以确定诱导高特异性CD8 T细胞反应是否与体外肿瘤识别、体内对已建立的黑色素瘤的治疗作用以及诱导表位扩散和自身免疫相关（特异性目的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. PUBLIC HEALTH RELEVANCE: One of the major obstacles for developing effective vaccines for treating cancer has been producing vaccines that induce strong immune responses against tumors. Unfortunately, most current vaccine types generate minimal immune responses and have little effect against established tumors. We have designed a novel vaccination approach that utilizes 3 basic components: 1) synthetic peptides (protein fragments) derived from tumor antigens that stimulate T lymphocytes; 2) potent immunological adjuvants that activate the immune system; and 3) immune stimulatory monoclonal antibodies that enhance the efficacy of T cells to react with tumor cells. Preliminary results in a mouse model of malignant melanoma using this vaccine, which we call TriVax (for its 3 basic components) demonstrates that this strategy is effective in inducing tumor-reactive T cells. 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). The results from these studies will serve as preclinical data that will allow us to take this approach into the clinic to treat human patients with melanoma and other types of cancer.