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 患有几种不同癌症类型的患者可以识别肿瘤细胞上呈递的肽抗原。 HLA I 类分子表面，触发特定的肿瘤细胞裂解。 相关抗原（TAA）可以通过多种途径直接促进肿瘤靶向治疗 干预措施，包括个性化疫苗、内源性 T 细胞输注或 TCR 工程 然而，只有少数人类 TAA 可以使用传统方法可靠地鉴定出来。 最近的证据表明这可能是由于大多数蛋白质组学方法。 免疫肽组由来自“非规范”来源的肽组成，例如衍生自 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，但其中很少有被验证为真正的靶标。 然而，克服非规范 TAA 识别所固有的挑战是关键。 有望显着扩大癌症患者靶向抗原的范围。 该项目的具体目标是识别和评估非规范 TAA 的潜力 黑色素瘤的治疗靶点，作为产生有效CTL的必要前提和基础 我们的中心假设是基于免疫疗法来治疗这种疾病。 典型的 TAA 可以构成共享的免疫治疗 CTL 靶标，并且这些 TAA 诱导 致癌驱动突变（例如 BRAF（V600E））的下游将表现出更大的肿瘤特异性，并且 我们根据显示的初步数据制定了这一假设。 可以使用高度敏感的集成来识别潜在的可靶向非典型 TAA 肽 质谱 (MS) 结合基因测序分析和新颖的内部生物信息学 我们还表明，组成性致癌 MAPK 通路激活会导致巨大的全球性后果。 肿瘤免疫肽组变化似乎可能涉及数千个非规范 TAA。 这项抗原发现工作具有强有力的临床依据，因为它将直接促进 基于 CTL 的新型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规范 TAA 并评估它们作为共同癌症靶点的免疫原性和潜在治疗价值。 还揭示了致癌介导的 MAPK 发生的转录组和蛋白质组变化 途径激活，以及这如何影响肿瘤免疫肽组最后，实现概述。 目标将产生重要的积极临床影响，因为它们将促进下一步的开发 为黑色素瘤患者开发基于抗原特异性 CTL 的新型免疫疗法，也可能 患有其他癌症类型的患者。