Developing Safe and Effective GD2-CAR T Cell Therapy for Diffuse Midline Gliomas

开发安全有效的 GD2-CAR T 细胞疗法治疗弥漫性中线胶质瘤

基本信息

批准号：
10463751
负责人：
Crystal Mackall
金额：
$ 64.44万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-06 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10463751
关键词：
Address Adrenal Cortex Hormones Adverse event Algorithms Animal Testing Animals Antigens Antitumor Response B lymphoid malignancy Biological Markers Biology Biometry Brain Neoplasms Brain Stem Glioma Brain Stem Neoplasms CAR T cell therapy CD47 gene Cancer Etiology Cells Cessation of life Characteristics Child Childhood Childhood Brain Neoplasm Childhood Malignant Brain Tumor Clinical Clinical Management Clinical Research Coin Collaborations Credentialing Data Diffuse intrinsic pontine glioma Disease Dose Dose-Limiting Edema Engineering Enrollment Ensure Event Exhibits Ganglioside GD2 Glean H3 K27M mutation Hematologic Neoplasms Histones Human Hydrocephalus Image Immunotherapy Inflammation Institution Intracranial Hypertension Intracranial Pressure Intravenous Investigation Machine Learning Magnetic Resonance Imaging Malignant Childhood Neoplasm Malignant Neoplasms Measures Mediating Monitor Mus Mutate Myelogenous Myeloid Cell Activation Myeloid Cells Neuroblastoma Outcome Patient-Focused Outcomes Patients Pediatric Neoplasm Phase Phase I Clinical Trials Pre-Clinical Model Preparation Progression-Free Survivals Radiation therapy Regimen Reporting Research Personnel Risk Safety Signal Transduction Solid Neoplasm Spinal Spinal Cord Standardization Supportive care Survival Rate Swelling T-Lymphocyte Testing Texture Therapeutic Toxic effect Translating Translations Treatment Efficacy Xenograft Model aged antitumor effect base bench to bedside bench-to-bedside translation cancer immunotherapy cell free DNA childhood cancer mortality chimeric antigen receptor chimeric antigen receptor T cells clinical efficacy cohort cytokine design diffuse midline glioma experience improved improved outcome insight machine learning algorithm macrophage mouse model neuro-oncology neurosurgery neurotoxicity novel novel strategies overexpression participant safety phase I trial pre-clinical preclinical study prevent radiological imaging radiomics resistance mechanism response single cell analysis tool trial design tumor tumor DNA tumor immunology young adult

项目摘要

PROJECT SUMMARY Brain tumors are the leading cause of cancer related death in children; among these, diffuse intrinsic pontine glioma (DIPG) and other histone-3 K27M (H3K27M) mutated diffuse midline gliomas (DMGs) are the most aggressive and are universally fatal with current standard therapies. Despite several decades of investigational trials testing dozens of therapeutic approaches, median overall survival for DIPG is 11 months. Chimeric antigen receptor (CAR)-expressing T-cells have mediated impressive clinical activity in B-cell malignancies, and recent preclinical and early clinical results suggest benefit in CNS malignancies. We discovered homogenous, high overexpression of the GD2 ganglioside on H3K27M DMGs and demonstrated impressive antitumor effects in xenograft models of H3K27M-mutant DIPG following treatment with GD2-CAR T cells (GD2-CART, Mount, Nat Med 2018). Significant clinical experience with GD2 targeting CAR T cells, available mostly from studies in neuroblastoma, demonstrate safety and some early signals of antitumor activity. Safe and effective translation of these findings to children with DMGs would transform the landscape for this universally lethal pediatric brain tumor. This bench-to-bedside-to-bench project will conduct three aims in parallel leveraging a recently launched single institution Phase I trial of GD2.BB.z.iCasp9-CAR T cells administered intravenously following a lymphodepleting preparative regimen in children and young adults with H3K27M DMGs. The first aim focuses on safety, integrating insights gleaned in our preclinical models into trial design to diminish the risk of tumor inflammation associated neurotoxicity (TIAN), to establish best practices and to develop improved grading and treatment algorithms for this novel toxicity. The second aim focuses on efficacy, assessing clinical activity of GD2-CART in DMG and identifying biomarkers and clinical features associated with response. We further address the limitations of standard radiographic imaging in these infiltrative tumors using a novel machine learning aided MRI radiomics approach to quantify textural changes within the tumor and assess whether such changes correlate with clinical outcome, and we assess whether GD2-CART induced changes in CSF cell free DNA can provide a rapid quantitative assessment of antitumor response. Our third aim is a discovery aim, focused on improving understanding of the biology associated with myeloid cell activation following GD2-CART therapy for DMGs, which we observe in preclinical models and we observed in the first patient treated. Here we undertake comprehensive single cell profiling of CSF myeloid cells emerging post-GD2-CART in patients enrolled on the study and in preclinical models, and bedside-to-bench translation using murine models to test the hypotheses that GD2-CART induced CNS myeloid cell expansion/activation limit the efficacy of GD2-CART, are modulated by corticosteroid therapy and that this obstacle can be overcome by engineering CD47 overexpression in the GD2-CART.

项目概要脑肿瘤是儿童癌症相关死亡的主要原因；其中，弥漫性固有脑桥胶质瘤 (DIPG) 和其他组蛋白 3 K27M (H3K27M) 突变的弥漫性中线胶质瘤 (DMG) 是最常见的具有攻击性，并且采用当前的标准疗法通常是致命的。尽管经过几十年的研究测试了数十种治疗方法的试验显示，DIPG 的中位总生存期为 11 个月。嵌合抗原表达受体（CAR）的 T 细胞在 B 细胞恶性肿瘤中介导了令人印象深刻的临床活性，并且最近临床前和早期临床结果表明对中枢神经系统恶性肿瘤有益。我们发现同质、高 H3K27M DMG 上 GD2 神经节苷脂的过度表达，并在使用 GD2-CAR T 细胞（GD2-CART、Mount、Nat 医学2018）。 GD2 靶向 CAR T 细胞的重要临床经验，主要来自以下研究：神经母细胞瘤，表现出安全性和一些抗肿瘤活性的早期信号。安全有效的翻译这些对患有 DMG 的儿童的研究结果将改变这种普遍致命的儿童大脑的面貌瘤。这个从实验室到临床到实验室的项目将利用最近启动的一项技术并行实现三个目标单一机构 GD2.BB.z.iCasp9-CAR T 细胞的 I 期试验使用 H3K27M DMG 的儿童和年轻人的淋巴细胞清除准备方案。第一个目标聚焦在安全性方面，将我们临床前模型中收集的见解融入试验设计中，以降低肿瘤风险炎症相关神经毒性（TIAN），建立最佳实践并制定改进的分级和这种新毒性的治疗算法。第二个目标侧重于疗效，评估临床活性 DMG 中的 GD2-CART 并识别与反应相关的生物标志物和临床特征。我们进一步使用新型机器解决这些浸润性肿瘤中标准放射成像的局限性学习辅助 MRI 放射组学方法可量化肿瘤内的纹理变化并评估是否存在这种变化变化与临床结果相关，我们评估 GD2-CART 是否诱导脑脊液无细胞变化 DNA 可以提供抗肿瘤反应的快速定量评估。我们的第三个目标是发现目标，专注于提高对 GD2-CART 后与骨髓细胞激活相关的生物学的理解 DMG 疗法，我们在临床前模型中观察到，并且在第一位接受治疗的患者中观察到。在这里我们对患者 GD2-CART 后出现的脑脊液骨髓细胞进行全面的单细胞分析参加了该研究和临床前模型，并使用小鼠模型进行床边到工作台的翻译以进行测试 GD2-CART 诱导 CNS 骨髓细胞扩增/激活的假设限制了 GD2-CART 的功效，受到皮质类固醇治疗的调节，并且可以通过改造 CD47 来克服这一障碍 GD2-CART 中的过度表达。