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

项目总结/摘要 该R 01申请的长期目标是为患有实体瘤的儿科患者开发有效的治疗方法。 使用表达嵌合抗原受体的T细胞（CAR T细胞）治疗肿瘤。复发性或 难治性实体瘤经历了令人沮丧的结果，尽管积极的管理与多模态 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 我建议用CAR T细胞靶向B7-H3，CAR T细胞是一种肿瘤相关抗原，在多种细胞上以高水平表达。 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41 BB配体（41 BBL），并且已经证明与标准B7-B7相比具有改善的抗肿瘤活性。 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细胞的给药是安全的并产生抗肿瘤作用。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 并提高其效力。这些假设将在两个相互关联的研究目标进行评估。目标1是 专注于翻译，实施I期临床试验，评估B7- 用于患有复发性或难治性B7-H3阳性实体瘤的儿科患者的表达41 BBL的H3-CAR T细胞。 目的2关注反向翻译，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 x scRNAseq分析和全基因组亚硫酸氢盐测序 通过免疫组化（WGBS）测定B7-H3-CAR T细胞的克隆结构和功能状态。肿瘤也将进行活检 以确定肿瘤微环境中B7-H3-CAR T细胞的存在和相互作用。根据结果 在这些相关的研究中，我们将实施一种策略来改善效应器功能/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。成功完成本报告中的拟议研究 R 01的应用将为实体瘤细胞治疗领域提供关键信息。而此应用程序 专注于靶向B7-H3阳性的儿科实体瘤，我们的发现可以很容易地应用于其他B7-H3阳性的儿科实体瘤。 H3阳性儿童和成人肿瘤，以及靶向不同肿瘤相关抗原的CAR T细胞疗法。

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.