Structural modeling of neoantigen presentation for rational design of heteroclitic neoepitope vaccines

新抗原呈递的结构模型，用于合理设计异位新表位疫苗

• 批准号: 10463222
• 负责人: Amanda L Huff
• 金额: $ 7.17万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10463222
• 关键词: Address; Affinity; Alleles; Amino Acid Sequence; Amino Acids; Antigens; Binding; Biological Assay; Biophysics; Cancer Burden; Cancer Patient; Cancer Vaccines; Cells; Characteristics; Clinical; Codon Nucleotides; Complex; Computer Models; Computer software; Data; Data Set; Development; Epitopes; Excision; Generations; HLA Antigens; Histocompatibility Antigens Class I; Human; Immune system; Immunotherapy; KRAS2 gene; KRASG12D; Libraries; Ligands; Malignant Neoplasms; Measurement; Mechanics; Modeling; Modification; Mutate; Mutation; Operative Surgical Procedures; Pancreatic Ductal Adenocarcinoma; Patient-Focused Outcomes; Patients; Peptide Vaccines; Peptides; Peripheral Blood Mononuclear Cell; Population; Privatization; Prognosis; Proteins; Resistance; Somatic Mutation; Structural Models; Structure; Survival Rate; T cell response; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Treatment outcome; Tumor Antigens; Vaccines; antigen binding; base; biophysical properties; cancer cell; cancer immunotherapy; cancer subtypes; cancer type; cancer vaccination; chemotherapy; clinical application; cohort; computational pipelines; computational platform; cytotoxic; design; exome sequencing; immunogenic; immunogenicity; improved; neoantigen vaccine; neoantigens; novel; rational design; refractory cancer; response; therapeutic vaccine; tumor; vaccine candidate

Project Summary Pancreatic ductal adenocarcinoma cancer (PDAC) is highly resistant to frontline surgical resection and chemotherapy treatments. Many treatment-resistant cancer types have benefited from immunotherapies that activate cytotoxic anti-tumor T cells against the somatic mutations, or neoantigens, expressed in cancer cells. One major challenge to the development of neoantigen-targeted immunotherapy for PDAC has been the low number and weakly immunogenic profile of identified neoantigens. Efficient activation of neoantigen-specific T cells is dependent on the recognition of 8- to 11-mer neoepitopes displayed on human leukocyte antigen (HLA) class I molecules. This recognition is the culmination of the biophysical and stereochemical contacts between the peptide, HLA, and T cell receptor (TCR) molecules. One mechanism to improve neoepitope immunogenicity is by modifying the peptide amino acid residues to enhance HLA binding or TCR recognition, thereby enhancing cognate T cell activation, while conserving reactivity to the parental epitope. These modified epitopes are termed heteroclitic epitopes. However, the stereochemical features of heteroclitic epitopes that enhance HLA binding or TCR recognition are understudied. Additionally, heteroclitic epitopes have been explored in the context of a limited number of HLA subtypes, restricting their development and application across patients. We hypothesize that rational design of heteroclitic neoepitope vaccines through structural modelling will improve T cell responses against PDAC neoantigens. To address this hypothesis, we will define the structural binding and spatial display dynamics of both shared and private PDAC heteroclitic neoepitopes in diverse HLAs. Among shared neoantigens expressed in PDAC, activating mutations in KRAS at codon 12 are present in up to 80% of PDAC tumors. In Specific Aim 1, we will interrogate the structural mechanics and immunogenic profile of heteroclitic KRAS G12D/V/C epitopes in a panel of 18, globally representative HLA subtypes. In Specific Aim 2, we will develop a computational pipeline to identify, prioritize and optimize patient- specific heteroclitic neoantigen vaccine candidates based on structural epitope features. We will use HLA binding measurements and T cell reactivity assays to validate immunogenic features of our computationally modelled heteroclitic epitopes. Together, these aims will define the structural features of immunogenic neoantigens in diverse HLAs, generate heteroclitic epitope vaccine candidates for shared and private PDAC antigens, and improve the therapeutic potential of cancer vaccines for hard-to-treat cancers such as PDAC.

项目摘要 胰腺导管腺癌癌（PDAC）对前线手术切除高度抗性 化学疗法治疗。许多耐药癌症类型都受益于免疫疗法 激活在癌细胞中表达的细胞毒性抗肿瘤T细胞或新抗原。 针对新抗原针对PDAC的免疫疗法的发展的主要挑战是很低 已鉴定的新抗原的数量和弱免疫原性。新抗原特异性T的有效激活 细胞取决于人类白细胞抗原（HLA）上显示的8至11-mer新皮肠的识别 I类分子。这种认识是生物物理和立体化学接触的顶点 肽，HLA和T细胞受体（TCR）分子。一种改善新皮标的机制 免疫原性是通过修饰肽氨基酸残基来增强HLA结合或TCR识别，即 从而增强了同源T细胞激活，同时保存对父母表位的反应性。这些修改了 表位称为杂志表位。但是，杂色表位的立体化学特征是 增强HLA结合或TCR识别被研究研究了。另外，杂级表位是 在有限数量的HLA子类型的背景下探索，限制了其开发和应用 跨患者。我们假设通过结构性的杂质新海皮疫苗的合理设计 建模将改善针对PDAC新抗原的T细胞反应。为了解决这一假设，我们将定义 结构结合和空间显示共享和私有PDAC杂级新皮标的动力学 多样化的HLA。在PDAC中表达的共同新抗原中，密码子12中的KRAS激活突变为 最多有80％的PDAC肿瘤。在特定目标1中，我们将审问结构力学和 杂体KRAS G12D/V/C表位的免疫原性在全球代表性HLA的面板中 亚型。在特定目标2中，我们将开发一条计算管道，以识别，优先和优化患者 - 基于结构表位特征的特定杂素新抗原疫苗候选物。我们将使用HLA 结合测量和T细胞反应性测定，以验证我们计算的免疫原性 建模的杂点表位。这些目标在一起将定义免疫原性的结构特征 新抗原在不同的HLAS中，生成共享和私人PDAC的杂质表位疫苗候选者 抗原，并提高癌症疫苗对PDAC等难以治疗的癌症的治疗潜力。