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.

项目总结 实体癌是儿童癌症相关死亡的主要原因，人们对治疗非常感兴趣。 免疫治疗在儿童实体瘤治疗中的研究进展免疫检查点抑制(ICI) 是成人实体肿瘤最活跃的免疫治疗形式，但ICI对儿童实体肿瘤无效。 这种差异的原因是儿科实体肿瘤的低突变负担，因为新抗原的产生 来自肿瘤的特定突变是ICI诱导的最有效的免疫反应的目标。过度表达 在正常生命组织中不表达的非突变自身抗原可以作为有效的基础 免疫疗法，但必须克服免疫耐受，以诱导对这类人的有效免疫反应 分子。该项目专注于尤文肉瘤(EWS)，这是一种低突变负担的实体肿瘤原型，用于 但这方面的进展已经停滞不前。EWS的标准治疗依赖于主要开发的剂量密集方案 20世纪70年代和80年代，给幸存者留下了严重的、终身的后遗症。目前还没有针对性的治疗方法 被证明是有效的。转移或复发的EWS患者很少存活。使用免疫多肽 在分析中，我们发现了来自脂肪酶-1(LIPI)和IGF2结合蛋白1(IGF2BP1)的新多肽，它们是 由人类白细胞抗原A2+在EWS上提出。这些非突变蛋白在绝大多数情况下都有高水平的过度表达 在重要的正常组织中基本上不存在，因此显示出一种非常有利的 免疫靶向。为了将这一发现转化为EWS的治疗应用，该项目应用了一种 我们开发的工作流程是为了发现、表征和设计针对这些目标的T细胞受体(TCR) 多肽。该项目解决的主要总体挑战是确定 鉴定和/或设计能够靶向自身抗原而不会引起交叉反应的高效TCR 这将导致不可接受的毒性。在目标1中，我们测试了TCR针对LIPI-和 IGF2BP1衍生肽将在HLA-A2+宿主中被鉴定，但由于免疫原因将表现出较低的效力 宽容。我们将同时发现和比较存在于HLA-A2宿主中的抗原反应性TCR， 我们预测将会更有效，但由于交叉反应可能是不安全的。在目标2中，我们使用下一代 将在人类白细胞抗原A2+宿主中鉴定的天然TCR改造成更有效但更安全的抗原特异性的方法 TCRs，通过亲和成熟或捕获键工程。鉴于已知的高反应性交叉反应风险 在这里开发的下一代工程TCR--Pigency TCR将在几个平台上进行严格审查 用于交叉反应。在目标3中，我们使用Mackall实验室开发的健身增强功能来增强功能 增强表达我们的候选LIPI和IGF2BP1反应的T细胞的效力 TCR。在这个项目中进行的工作将提供最先进的治疗方法，准备在 并提供有关以自我为目标的TCR工程的最佳方法的一般理解 抗原，这将提供价值的儿科肿瘤学和低突变负担癌症超越EWS。