Treatment of Melanoma with Optimzed Peptide Vaccines

描述(由申请人提供)：开发有效的癌症治疗性疫苗的一个主要挑战是克服对肿瘤相关抗原的免疫耐受。由于耐受，高亲和力的CD8T淋巴细胞是识别和杀伤肿瘤细胞的效应者，不能被常规疫苗诱导。我们设计了一种新的疫苗接种方法，利用代表CD8T细胞表位的合成肽、作为强大免疫佐剂的Toll样受体激动剂和免疫共刺激单抗。在使用这种疫苗的小鼠黑色素瘤模型中的初步数据表明，这种策略在诱导具有治疗效果的肿瘤反应性CD8T细胞方面是有效的。在这里，我们建议开展TriVax的优化研究，以证明该方法的临床可行性(具体目标1)。我们将进行实验，进一步优化TriVax，目的是开发一种有效的晚期肿瘤疫苗(特定目标2)。最后，我们将通过研究几个潜在的CD8T细胞表位的反应来验证TriVax免疫策略的使用，以确定高亲和力CD8T细胞反应的诱导是否与体外肿瘤识别、体内对已建立的黑色素瘤的治疗效果以及与诱导表位扩散和自身免疫(特定目标3)相关。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。 与公共卫生相关：开发有效的癌症治疗疫苗的主要障碍之一是生产能够诱导对肿瘤的强烈免疫反应的疫苗。不幸的是，目前大多数类型的疫苗产生的免疫反应最小，对已建立的肿瘤几乎没有效果。我们设计了一种新的疫苗接种方法，它使用3种基本成分：1)来自肿瘤抗原的合成肽(蛋白质片段)，刺激T淋巴细胞；2)有效的免疫佐剂，激活免疫系统；3)免疫刺激单抗，增强T细胞与肿瘤细胞的反应效率。在小鼠恶性黑色素瘤模型中使用这种疫苗的初步结果表明，这种策略在诱导肿瘤反应性T细胞方面是有效的。我们称之为TriVax(因为它的3个基本成分)。在这里，我们建议开展TriVax的优化研究，以证明该方法的临床可行性(具体目标1)。我们将进行实验，进一步优化TriVax，目的是开发一种有效的晚期肿瘤疫苗(特定目标2)。最后，我们将通过研究几个潜在的CD8T细胞表位的反应来验证TriVax免疫策略的使用，以确定高亲和力CD8T细胞反应的诱导是否与体外肿瘤识别、体内对已建立的黑色素瘤的治疗效果以及与诱导表位扩散和自身免疫(特定目标3)相关。这些研究的结果将作为临床前数据，使我们能够将这种方法应用于临床，治疗患有黑色素瘤和其他类型癌症的人类患者。

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.