Treatment of Melanoma with Optimzed Peptide Vaccines

用优化肽疫苗治疗黑色素瘤

• 批准号: 8256543
• 负责人: Esteban Celis
• 金额: $ 33.61万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8256543
• 关键词: Address; Adjuvant; Agonist; Antibodies; Antigens; Autoimmunity; Avidity; CD8-Positive T-Lymphocytes; CD8B1 gene; Cancer Patient; Cells; Clinic; Clinical; Data; Elements; Epitopes; Goals; Human; Immune; Immune response; Immune system; Immunization; Immunologic Adjuvants; In Vitro; Individual; Malignant Neoplasms; Monoclonal Antibodies; Mus; Patients; Peptide Vaccines; Peptides; Procedures; Protein Fragment; Signal Transduction; T cell response; T-Lymphocyte; T-Lymphocyte Epitopes; Therapeutic; Therapeutic Effect; Toll-like receptors; Tumor Antigens; Tumor Burden; Vaccination; Vaccines; Vitiligo; cancer type; design; in vivo; killings; melanoma; mouse model; neoplastic cell; novel; pre-clinical; public health relevance; research study; response; synthetic peptide; therapeutic effectiveness; therapeutic vaccine; treatment response; tumor; tumor growth; vaccination strategy

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.

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CD 8 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CD 8 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CD 8 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CD 8 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CD 8 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。 公共卫生相关性：开发治疗癌症的有效疫苗的主要障碍之一是生产诱导针对肿瘤的强烈免疫应答的疫苗。不幸的是，目前大多数疫苗类型产生最小的免疫反应，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，该方法利用3种基本成分：1）源自刺激T淋巴细胞的肿瘤抗原的合成肽（蛋白质片段）; 2）激活免疫系统的有效免疫佐剂; 3）增强T细胞与肿瘤细胞反应功效的免疫刺激性单克隆抗体。使用这种疫苗的恶性黑色素瘤小鼠模型的初步结果表明，这种策略在诱导肿瘤反应性T细胞方面是有效的。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CD 8 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CD 8 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）。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。