Attacking the Immunopeptidome of Ewing Sarcoma

攻击尤文肉瘤的免疫肽组

基本信息

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
项目类别：
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

项目摘要

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.

项目概要实体癌是儿童癌症相关死亡的主要原因，人们对利用实体癌非常感兴趣免疫检查点抑制（ICI）治疗儿童实体瘤的最新进展。是治疗成人实体瘤最活跃的免疫疗法，但 ICI 对儿童实体瘤无效。这种差异可以用儿科实体瘤的低突变负荷来解释，因为新抗原的产生肿瘤特异性突变是 ICI 诱导的最有效免疫反应的目标。未突变的自身抗原，在正常重要组织上不表达，可以作为有效的基础免疫疗法，但必须克服免疫耐受才能诱导对此类药物的有效免疫反应该项目重点关注尤文肉瘤（EWS），一种原型低突变负荷实体瘤，用于治疗 EWS 的标准疗法主要依赖于剂量密集型治疗方案，但进展已经停滞。 20 世纪 70 年代和 80 年代，幸存者遭受严重的、终生的晚期影响。使用免疫肽组，很少有转移性或复发性 EWS 患者能够存活。通过分析，我们发现了来自脂肪酶 1 (LIPI) 和 IGF2 结合蛋白 1 (IGF2BP1) 的新肽，它们这些非突变蛋白在 EWS 上呈高水平过度表达。 EWS 的存在，并且在重要的正常组织中基本上不存在，从而表现出非常有利的特征为了将这一发现转化为 EWS 的治疗应用，该项目应用了我们开发的工作流程是为了发现、表征和设计针对这些的 T 细胞受体 (TCR) 该项目解决的主要挑战是确定肽的最佳方法。识别和/或设计能够靶向自身抗原而不引起交叉反应的高效 TCR 在目标 1 中，我们测试了针对 LIPI- 和的 TCR 的假设。 IGF2BP1 衍生肽将在 HLA-A2+ 宿主中被识别，但由于免疫原因而表现出低效力我们将同时发现并比较 HLA-A2– 宿主中存在的抗原反应性 TCR，这我们预测会更有效，但由于交叉反应可能不安全。在目标 2 中，我们使用下一代。将 HLA-A2+ 宿主中鉴定的天然 TCR 改造为更有效但更安全的抗原特异性的方法鉴于已知的高交叉反应性风险，TCR 通过亲和力成熟或捕获键工程。效力 TCR，此处开发的下一代工程 TCR 将在多个平台上进行严格审查在目标 3 中，我们使用 Mackall 实验室开发的健身增强功能来增强效力。 CAR T 细胞增强表达我们的主要候选 LIPI 和 IGF2BP1 反应性的 T 细胞的效力该项目中进行的工作将提供最先进的治疗方法，为临床测试做好准备。 EWS 并提供关于设计针对自我的 TCR 的最佳方法的一般理解抗原，这将为儿科肿瘤学和 EWS 之外的低突变负荷癌症提供价值。