Identification and assessment of unconventional tumor-associated antigens as potential targets for cytotoxic T-cell based immunotherapy of cancer

鉴定和评估非常规肿瘤相关抗原作为基于细胞毒性 T 细胞的癌症免疫疗法的潜在靶标

• 批准号: 10655279
• 负责人: PATRICK HWU
• 金额: $ 56.96万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10655279
• 关键词: Antigen Presentation; Antigen Targeting; Antigens; Applications Grants; BRAF gene; Bioinformatics; Cancer Patient; Categories; Cell surface; Cellular immunotherapy; Clinical; Cytolysis; Cytotoxic T-Lymphocytes; DNA; Data; Detection; Development; Disease; Engineering; Epitopes; Foundations; Genetic; Goals; Human; Immune; Immunotherapeutic agent; Immunotherapy; Infusion procedures; Interleukin-2; Intervention; Introns; Knowledge; Leukocytes; MAP Kinase Gene; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Melanoma Cell; Methodology; Methods; Minority; Mitogen-Activated Protein Kinases; Nature; Oncogenic; Pathway interactions; Patients; Peptide Vaccines; Peptides; Phosphopeptides; Post-Translational Protein Processing; Proteomics; RNA Editing; RNA Splicing; Refractory; Reporting; Research; Safety; Source; Specificity; T cell therapy; T-Cell Receptor; T-Lymphocyte; Techniques; Therapeutic; Translating; Tumor Antigens; Tumor-Infiltrating Lymphocytes; Vaccines; Work; bioinformatics pipeline; cancer immunotherapy; cancer therapy; cancer type; cytotoxic; design; driver mutation; immunogenic; immunogenicity; innovation; melanoma; multicatalytic endopeptidase complex; neoplastic cell; next generation; novel; personalized immunotherapy; success; therapeutic target; transcriptome sequencing; transcriptomics; tumor; tumor specificity

PROJECT SUMMARY / ABSTRACT: Cytotoxic T lymphocyte (CTL)-based immunotherapies have shown great success in the treatment of patients with several different cancer types. CTLs recognize peptide antigens presented at the tumor cell surface by HLA class I molecules, triggering specific tumor cell lysis. Defining the nature of such tumor- associated antigens (TAAs) can directly facilitate therapeutic tumor targeting through a number of interventions, including personalized vaccines, endogenous T cell infusion, or TCR-engineered immunotherapies. However, only a minority of human TAAs can be confidently identified using conventional proteomic methodologies. Recent evidence suggests this may be due to the fact that most of the immunopeptidome is comprised of peptides derived from ‘non-canonical’ sources such as those derived from translated introns, RNA editing, proteasome splicing, or containing post-translational modifications. Although these represent potentially high value tumor targets, few of these have yet been validated as bona fide TAAs. However, overcoming the challenges inherent in non-canonical TAA identification holds the promise of significantly expanding the landscape of targetable antigens for cancer patients. The specific objective of this project is to identify and assess non-canonical TAAs as potential therapeutic targets for melanoma, as a necessary prerequisite and foundation for generating effective CTL- based immunotherapies for treating patients with this disease. It is our central hypothesis that unique, non- canonical TAAs can constitute shared immunotherapeutic CTL targets, and that those TAAs induced downstream of oncogenic driver mutations such as BRAF(V600E) will show greater tumor specificity and refractoriness to antigen loss. We have formulated this hypothesis based on preliminary data showing that potentially targetable non-canonical TAA peptides can be identified using an integration of highly sensitive mass spectrometry (MS) combined with genetic sequencing analysis and a novel, in-house bioinformatics pipeline. We have also shown that constitutive oncogenic MAPK pathway activation leads to dramatic global tumor immunopeptidome shifts that appear to potentially involve thousands of non-canonical TAAs. There is a strong clinical rationale for this antigen discovery work since it will directly facilitate the development of novel, CTL-based therapies with the potential to benefit large numbers of cancer patients. The proposed work is innovative, because it will explore different categories of non-canonical TAAs in cancer and assess their immunogenicity and potential therapeutic value as shared cancer targets. It will also shed light on the transcriptomic and proteomic changes that occur upon oncogenic-mediated MAPK pathway activation, and how this influences the tumor immunopeptidome. Lastly, fulfilling the outlined objectives will have an important positive clinical impact, because they will facilitate development of the next generation of novel antigen-specific CTL-based immunotherapies for melanoma patients, and possibly also patients with other cancer types.

项目摘要 /摘要： 基于细胞毒性T淋巴细胞（CTL）的免疫疗法在治疗方面取得了巨大成功 患有几种癌症类型的患者。 CTL识别在肿瘤细胞上呈现的肽抗原 HLA I类分子的表面，触发特定的肿瘤细胞裂解。定义这种肿瘤的性质 相关抗原（TAA）可以直接促进通过多个的治疗性肿瘤靶向 干预措施，包括个性化疫苗，内源性T细胞输注或TCR工程 免疫疗法。但是，只能使用常规的 蛋白质组学方法。最近的证据表明，这可能是由于大多数 免疫肽组由源自“非典型”来源的胡椒体组成，例如 来自翻译的内含子，RNA编辑，蛋白酶体剪接或包含翻译后修饰。 尽管这些代表了潜在的高价值肿瘤靶标，但其中很少有人被证实为BONA fide taas。但是，克服非规范taa识别中固有的挑战使得 有望显着扩大癌症患者靶向抗原的景观。 该项目的具体目标是识别和评估非规范的TAA作为潜力 黑色素瘤的治疗靶标，是产生有效CTL-的必要先决条件和基础 基于治疗该疾病患者的免疫疗法。我们的中心假设是独特的，非 - 规范TAA可以构成共享的免疫治疗CTL靶标，并且这些TAA诱导 诸如BRAF（V600E）等致癌驱动器突变的下游将显示出更大的肿瘤特异性，并且 对抗原损失的折射率。我们已经根据初步数据提出了这一假设。 可以通过高度敏感 质谱（MS）与遗传测序分析和新型内部生物信息学结合 管道。我们还表明，本构肿瘤MAPK途径激活导致戏剧性的全局 肿瘤免疫肽组的转移似乎可能涉及数千种非典型的TAA。有 这项抗原发现工作的强大临床原理，因为它将直接支持 新型基于CTL的疗法，有可能使大量癌症患者受益。 拟议的工作具有创新性，因为它将探索不同类别的非典型TAA 在癌症中，并评估其免疫原性和潜在的治疗价值作为共同的癌症靶标。会 还阐明了在致癌介导的MAPK时发生的转录组和蛋白质组学变化 途径激活，以及这如何影响肿瘤免疫肽组。最后，满足概述 目标将产生重要的积极临床影响，因为它们将促进下一个的发展 用于黑色素瘤患者的新型抗原特异性CTL免疫疗法的产生，也可能 患有其他癌症类型的患者。