Attacking the Immunopeptidome of Ewing Sarcoma

攻击尤文肉瘤的免疫肽组

• 批准号: 10714230
• 负责人: Sabine Heitzeneder
• 金额: $ 46.74万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-11 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10714230
• 关键词: Address; Adoptive Cell Transfers; Adoptive Transfer; Adult; Affinity; Antigens; Autoantigens; Binding; Binding Proteins; Bone neoplasms; CRISPR/Cas technology; Cancer Burden; Cancer Etiology; Chemoresistance; Child; Childhood Solid Neoplasm; Data; Dendritic Cells; Development; Disease; Dose; Engineering; Ewings sarcoma; HLA-A2 Antigen; IGF2 gene; Immune Targeting; Immune Tolerance; Immune response; Immune system; Immunotherapeutic agent; Immunotherapy; Incidence; Individual; Knock-out; Knowledge; Late Effects; Lead; Lipase; Longevity; Malignant Neoplasms; Mediating; Metastatic/Recurrent; Mission; Mutation; Nature; Nonmetastatic; Normal tissue morphology; Oncogenes; Outcome; Patients; Pediatric Neoplasm; Pediatric Oncology; Peptides; Process; Proteins; Public Health; Quality of life; Recurrence; Regimen; Research; Resistance; Risk; Safety; Science; Severities; Signal Transduction; Solid; Solid Neoplasm; Survival Rate; Survivors; T cell therapy; T-Cell Receptor; T-Lymphocyte; Technology; Testing; Therapeutic; Time; Tissues; Toxic effect; Translating; Tumor Antigens; Tumor Cell Derivative Vaccine; United States National Institutes of Health; Variant; Work; antigen-specific T cells; autologous lymphocytes; bench to bedside; cancer cell; candidate identification; checkpoint inhibition; chemotherapy; childhood cancer mortality; chimeric antigen receptor T cells; comparison control; cross reactivity; effector T cell; engineered T cells; exhaustion; experience; fitness; high risk; immunotherapy trials; improved outcome; interest; lead candidate; neoantigens; next generation; novel; novel strategies; novel therapeutics; overexpression; postnatal; prevent; prototype; research clinical testing; screening; targeted treatment; therapeutic candidate; therapeutic evaluation; tumor

PROJECT SUMMARY Solid cancers are a leading cause of cancer related death in children and there is great interest in harnessing recent progress in immunotherapy for the treatment of pediatric solid tumors. Immune checkpoint inhibition (ICI) is the most active form of immunotherapy for adult solid cancers, but ICI is not effective in pediatric solid tumors. This discrepancy is explained by the low mutational burden of pediatric solid tumors, since neoantigens arising from tumor specific mutations are the target of the most potent ICI induced immune responses. Overexpressed non-mutated self-antigens, that are not expressed on normal vital tissues, can serve as the basis for effective immune therapies, but immune tolerance must be overcome to induce potent immune responses to this class of molecules. This project focuses on Ewing Sarcoma (EWS) a prototype low mutation burden solid tumor, for which progress has stalled. Standard therapies for EWS rely on dose intensive regimens largely developed in the 1970s and 80s which leave survivors with severe, lifelong late effects. No targeted therapeutics have been demonstrated to be effective. Few patients with metastatic or recurrent EWS survive. Using immunopeptidome profiling, we discovered novel peptides from lipase-1 (LIPI) and IGF2 binding protein 1 (IGF2BP1) that are presented by HLA-A2+ on EWS. These non-mutant proteins are overexpressed at high levels in the vast majority of EWS and are essentially absent from vital normal tissues, thereby demonstrating a very favorable profile for immune targeting. To translate this discovery into a therapeutic application for EWS, this project applies a workflow we developed to discover, characterize, and engineer T cells receptors (TCRs) targeting these peptides. The major overarching challenge that the project addresses is determining the optimal approach to identify and/or engineer high potency TCRs capable of targeting self-antigens without incurring cross-reactivity that would result in unacceptable toxicity. In Aim 1, we test the hypothesis that TCRs targeting LIPI- and IGF2BP1-derived peptides will be identified in HLA-A2+ hosts but will manifest low potency due to immune tolerance. We will simultaneously discover and compare antigen reactive TCRs present in HLA-A2– hosts, which we predict will be more potent, but may be unsafe due to cross-reactivity. In Aim 2, we use next generation approaches to engineer natural TCRs, identified in HLA-A2+ hosts, into more potent, but safe antigen-specific TCRs, through affinity maturation or catch bond engineering. Given the known risks for cross reactivity of high potency TCRs, next generation engineered TCRs developed here will be closely vetted across several platforms for cross-reactivity. In Aim 3, we use fitness enhancements developed in the Mackall lab to enhance the potency of CAR T cells to enhance the potency of T cells expressing our lead candidate LIPI- and IGF2BP1-reactive TCRs. The work conducted in this project will deliver state-of-the-art therapeutics ready for clinical testing in EWS and provide general understanding regarding the optimal approach to engineer TCRs targeting self- antigens, which will provide value in pediatric oncology and low mutation burden cancers beyond EWS.

项目摘要 固体癌症是儿童癌症与癌症有关的主要原因，并且有兴趣利用 免疫疗法治疗小儿实体瘤的最新进展。免疫检查点抑制（ICI） 是成年固体癌症的免疫疗法最活跃的形式，但ICI在小儿实体瘤中无效。 这种差异是通过小儿实体瘤的低突变燃烧来解释的 来自肿瘤特异性突变是最有效的ICI诱导免疫反应的靶标。过表达 未在正常重要组织上表达的非突变自抗原可以作为有效的基础 免疫疗法，但必须克服免疫耐受性，以诱导对此类别的有效免疫反应 分子。该项目着重于尤因肉瘤（EWS）原型低突变燃烧实体瘤，用于 哪个进展停滞了。 EWS的标准疗法依赖于剂量密集型方案很大程度上开发了 1970年代和80年代，生存具有严重的终身后期影响。没有针对性的治疗 被证明是有效的。很少有转移性或经常性EWS的患者能够生存。使用免疫肽组 分析，我们发现了脂肪酶-1（LIPI）和IGF2结合蛋白1（IGF2BP1）的新肽 由HLA-A2+在EWS上提出。这些非突变蛋白在绝大多数的高水平中过表达 EWS的属性，本质上是重要的正常组织，从而证明了非常有利的特征 免疫靶向。为了将此发现转化为EWS的治疗应用程序，此项目应用了 我们开发的工作流程旨在发现，表征和工程T细胞受体（TCR）针对这些 肽。该项目解决的主要总体挑战是确定最佳方法 识别和/或工程师高效力TCR，能够靶向自我抗原而不会产生交叉反应性 这将导致不可接受的毒性。在AIM 1中，我们检验了靶向Lipi和的TCR的假设 IGF2BP1衍生的肽将在HLA-A2+宿主中识别，但由于免疫而表现出低效力 宽容。我们将简单地发现并比较HLA-A2-宿主中存在的抗原反应性TCR， 我们预测，由于交叉反应性，可能会不安全。在AIM 2中，我们使用下一代 在HLA-A2+宿主中识别的工程师天然TCR的方法，具有更大但安全的抗原特异性 TCR，通过亲和力成熟或捕获债券工程。鉴于已知的高反应风险 效力TCRS，下一代工程的TCR在这里开发的TCR将在几个平台上进行密切审查 用于交叉反应性。在AIM 3中，我们使用Mackall Lab中开发的健身增强功能来增强效力 CAR T细胞增强表达我们铅候选脂肪和IGF2BP1反应的T细胞的效力 TCR。该项目进行的工作将提供最新的治疗疗法，以准备进行临床测试 EWS并提供有关针对自我的最佳方法的最佳方法的一般理解 抗原将提供小儿肿瘤学和低突变伯嫩癌的价值。