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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要 R01应用的长期目标是为患有实体瘤的儿科患者开发一种有效的治疗方法。使用表达嵌合抗原受体的 T 细胞（CAR T 细胞）治疗肿瘤。复发或复发的儿科患者尽管采用多模式积极治疗，难治性实体瘤仍经历令人沮丧的结果疗法和 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。我们提议用 CAR T 细胞靶向 B7-H3，CAR T 细胞是一种在多种细胞上高水平表达的肿瘤相关抗原。儿科实体瘤，在大多数正常组织中表达有限。我们开发了B7-H3-CAR T细胞表达 41BB 配体 (41BBL)，并且与标准 B7- 相比，已证明抗肿瘤活性有所提高临床前模型中的 H3-CAR T 细胞。我们现在希望在临床上评估我们的方法并假设 B7-H3-CAR T 细胞的施用是安全的，并且具有抗肿瘤作用。次要假设包括需要精心策划的相关研究来破译人类 CAR T 细胞生物学并提高他们的效力。这些假设将在两个相关的研究目标中进行评估。目标 1 是专注于转化，实施评估 B7- 安全性和抗肿瘤活性的 I 期临床试验表达 41BBL 的 H3-CAR T 细胞用于治疗患有复发或难治性 B7-H3 阳性实体瘤的儿科患者。目标 2 侧重于反向翻译，评估 B7-H3-CAR T 细胞的体内扩增和持久性。它将执行单细胞 (sc) TCR 分析、10x scRNAseq 分析和全基因组亚硫酸氢盐测序 (WGBS) 确定 B7-H3-CAR T 细胞的克隆结构和功能状态。肿瘤也将进行活检确定 B7-H3-CAR T 细胞在肿瘤微环境中的存在和相互作用。根据结果在这些相关研究中，我们将实施一项策略来改善效应功能/抗肿瘤活性 B7-H3-CAR T 细胞并在临床前模型中对其进行评估。成功完成本次拟议的研究 R01的应用将为实体瘤细胞治疗领域提供关键信息。虽然这个应用程序专注于针对 B7-H3 阳性儿童实体瘤，我们的研究结果可以很容易地应用于其他 B7- H3 阳性儿童和成人肿瘤，以及针对不同肿瘤相关抗原的 CAR T 细胞疗法。