Enhancing B7-H3-CAR T cell therapy for pediatric solid tumors

增强儿童实体瘤的 B7-H3-CAR T 细胞疗法

• 批准号: 10444380
• 负责人: Christopher C. DeRenzo
• 金额: $ 73.41万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10444380
• 关键词: Adoptive Transfer; Adult; Antigen Targeting; Antigens; Applications Grants; Biology; Biopsy; Brain Neoplasms; CD19 gene; CD276 gene; CD28 gene; Cell Therapy; Cell surface; Cells; Child; Childhood; Childhood Solid Neoplasm; Clinical; Clinical Research; Clinical Trials; Combined Modality Therapy; Correlative Study; Data; Disease; Ensure; Goals; Human; Immune; Immunotherapy; Infusion procedures; Learning; Ligands; Malignant Neoplasms; Maximum Tolerated Dose; Morbidity - disease rate; Neuroblastoma; Normal tissue morphology; Outcome; Patient-Focused Outcomes; Patients; Phase; Phase I Clinical Trials; Population; Pre-Clinical Model; Production; Protocols documentation; Refractory; Relapse; Reproducibility; Research; Rhabdomyosarcoma; Safety; Signal Transduction; Solid Neoplasm; Structure; Survival Rate; T cell therapy; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Testing; Text; Therapeutic; Translations; Treatment Failure; Tumor Antigens; antitumor effect; base; bisulfite sequencing; chimeric antigen receptor; chimeric antigen receptor T cells; cytokine; design; effective therapy; engineered T cells; experience; high risk; improved; improved outcome; in vivo; insight; mortality; osteosarcoma; pediatric patients; pre-clinical; prevent; research clinical testing; success; targeted treatment; tumor; tumor microenvironment; whole genome

PROJECT SUMMARY/ABSTRACT The long-term goal of this R01 application is to develop an effective therapy for pediatric patients with solid tumors using T cells expressing chimeric antigen receptors (CAR T cells). Pediatric patients with relapsed or refractory solid tumors experience dismal outcomes despite aggressive management with multimodality therapies, and T cell immunotherapy has the potential to improve outcomes for these challenging diseases. We propose to target B7-H3 with CAR T cells, a tumor associated antigen that is expressed at high levels on multiple pediatric solid tumors, with limited expression in most normal tissues. We have developed B7-H3-CAR T cells expressing 41BB ligand (41BBL), and have demonstrated improved antitumor activity compared to standard B7- H3-CAR T cells in preclinical models. We now wish to evaluate our approach clinically and hypothesize that the administration of B7-H3-CAR T cells is safe and results in antitumor effects. Secondary hypotheses include that carefully orchestrated correlative studies are needed to decipher human CAR T cell biology and improve their potency. These hypotheses will be evaluated in two interrelated research aims. Aim 1 is focused on translation, implementing a Phase I clinical trial evaluating the safety and antitumor activity of B7- H3-CAR T cells expressing 41BBL for pediatric patients with relapsed or refractory B7-H3-positive solid tumors. Aim 2 is focused on reverse translation, assessing the in vivo expansion and persistence of B7-H3-CAR T cells. It will perform single cell (sc) TCR analysis, 10x scRNAseq analysis and whole genome bisulfite sequencing (WGBS) to determine the clonal structure and functional state of B7-H3-CAR T cells. Tumors will also be biopsied to determine B7-H3-CAR T cell presence and interactions within the tumor microenvironment. Based on results of these correlative studies, we will implement one strategy to improve the effector function/antitumor activity of B7-H3-CAR T cells and evaluate it in preclinical models. Successful completion of the proposed studies in this R01 application will provide critical information for the field of cell therapy for solid tumors. While this application is focused on targeting B7-H3-positive pediatric solid tumors, our findings could be readily applied to other B7- H3-positive pediatric and adult tumors, and CAR T cell therapies targeting different tumor associated antigens.

项目摘要/摘要 这个R01应用程序的长期目标是开发一种有效的治疗儿童患者的固体 使用表达嵌合抗原受体的T细胞(CAR T细胞)的肿瘤。复发或复发的儿童患者 难治性实体肿瘤尽管采用积极的多模式治疗，但结果令人沮丧 治疗，T细胞免疫疗法有可能改善这些具有挑战性的疾病的结果。我们 建议用CAR T细胞靶向B7-H3，CAR T细胞是一种高水平表达的肿瘤相关抗原，在 儿童实体瘤，在大多数正常组织中表达有限。我们已经研制出B7-H3-CAR T细胞 表达41BB配体(41BBL)，并显示出比标准B7-1更强的抗肿瘤活性 临床前模型中的H3-CAR T细胞。我们现在希望对我们的方法进行临床评估，并假设 使用B7-H3-CAR T细胞是安全的，并且具有抗肿瘤作用。次要假设 包括需要精心策划相关研究来破译人类汽车T细胞生物学 并提高它们的效力。这些假设将在两个相互关联的研究目标中进行评估。目标1是 专注于翻译，实施I期临床试验，评估B7-B7的安全性和抗肿瘤活性 B7-H3阳性实体瘤复发或难治性患儿表达41BBL的H3-CAR T细胞 AIM 2专注于反向翻译，评估B7-H3-CAR T细胞的体内扩增和持久性。 它将进行单细胞(Sc)TCR分析、10倍scRNAseq分析和全基因组亚硫酸盐测序 (WGBS)测定B7-H3-CAR T细胞的克隆结构和功能状态。肿瘤也将被活组织检查。 确定B7-H3-CAR T细胞在肿瘤微环境中的存在和相互作用。以结果为基础 在这些相关的研究中，我们将实施一个策略来提高效应功能/抗肿瘤活性 B7-H3-CAR T细胞，并在临床前模型中进行评估。圆满完成这项建议的研究 R01的应用将为实体瘤的细胞治疗领域提供关键信息。虽然此应用程序 专注于针对B7-H3阳性的儿童实体瘤，我们的发现可以很容易地应用于其他B7-H3- H3阳性的儿童和成人肿瘤，以及针对不同肿瘤相关抗原的CAR T细胞治疗。