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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要胰腺导管腺癌（PDAC）对一线手术切除具有高度抵抗力，化疗治疗。许多难治性癌症类型已受益于免疫疗法激活细胞毒性抗肿瘤 T 细胞对抗癌细胞中表达的体细胞突变或新抗原。开发针对 PDAC 的新抗原靶向免疫疗法的一大挑战是低已鉴定的新抗原的数量和弱免疫原性特征。有效激活新抗原特异性 T 细胞依赖于对人类白细胞抗原 (HLA) 上展示的 8 至 11 聚体新表位的识别 I 类分子。这种认识是生物物理和立体化学接触的顶峰肽、HLA 和 T 细胞受体 (TCR) 分子。改善新表位的一种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，从而增强同源 T 细胞的激活，同时保留对亲本表位的反应性。这些修改过的表位被称为异斜表位。然而，异斜表位的立体化学特征增强 HLA 结合或 TCR 识别的作用尚待研究。此外，异斜表位已被在有限数量的 HLA 亚型的背景下进行探索，限制了它们的开发和应用跨患者。我们假设通过结构合理设计异位新表位疫苗建模将改善 T 细胞针对 PDAC 新抗原的反应。为了解决这个假设，我们将定义共享和私有 PDAC 异位新表位的结构结合和空间显示动态不同的 HLA。在 PDAC 中表达的共享新抗原中，KRAS 密码子 12 处的激活突变是存在于高达 80% 的 PDAC 肿瘤中。在具体目标 1 中，我们将探讨结构力学和一组 18 个具有全球代表性的 HLA 中异簇 KRAS G12D/V/C 表位的免疫原性特征亚型。在具体目标 2 中，我们将开发一个计算管道来识别、优先排序和优化患者基于结构表位特征的特定异源新抗原候选疫苗。我们将使用 HLA 结合测量和 T 细胞反应性测定，以验证我们的计算免疫原性特征模拟异斜表位。这些目标共同将定义免疫原性的结构特征不同 HLA 中的新抗原，为共享和私有 PDAC 生成异位表位候选疫苗抗原，并提高癌症疫苗对 PDAC 等难治性癌症的治疗潜力。