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：
10679077
负责人：
Crystal Mackall
金额：
$ 65.84万
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/10679077
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 Eligibility Determination Engineering Enrollment Ensure Event Exhibits Ganglioside GD2 Glean Hematologic Neoplasms Histones Human Hydrocephalus Image Immunotherapy Inflammation Institution Intracranial Hypertension Intracranial Pressure Machine Learning Macrophage 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 Progression-Free Survivals Radiation therapy Recommendation 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 Vertebral column Xenograft Model aged antitumor effect bench to bedside bench-to-bedside translation biomarker identification 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 intravenous administration machine learning algorithm mouse model mutant neuro-oncology neurosurgery neurotoxicity novel novel strategies overexpression participant enrollment participant safety phase I trial pre-clinical preclinical study prevent radiological imaging radiomics resistance mechanism response safety assessment 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.

项目摘要脑肿瘤是儿童癌症相关死亡的主要原因。其中，弥漫性固有神经胶质瘤（DIPG）和其他组蛋白-3 K27M（H3K27M）突变的弥漫性中线神经胶质瘤（DMG）是最多的具有侵略性，并具有当前标准疗法的普遍致命。尽管进行了数十年的研究试验测试了数十种治疗方法，DIPG的总体存活率中位数为11个月。嵌合抗原表达T细胞受体（CAR）在B细胞恶性肿瘤中具有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中枢神经系统恶性肿瘤有益。我们发现了同质，高 H3K27M DMG上GD2神经苷的过表达，并在表现出令人印象深刻的抗肿瘤作用用GD2-CAR T细胞处理后，H3K27M突变型DIPG的异种移植模型（GD2-CART，MONT，NAT Med 2018）。具有GD2靶向CAR T细胞的临床经验的大量临床经验，主要可从研究中获得神经母细胞瘤表明安全性和抗肿瘤活性的一些早期信号。安全有效的翻译这些发现给患有DMG的儿童将改变这种致命的小儿大脑的景观瘤。这个基准对基础项目将实现三个目标，以并行利用最近启动的 GD2.BB.Z.ICASP9-CAR T细胞的单个机构I期试验在A静脉内给药。 H3K27M DMGS的儿童和年轻人中的淋巴结蛋白制备方案。第一个目的是重点关于安全性，将我们的临床前模型中收集的见解集成到试验设计中，以降低肿瘤的风险与炎症相关的神经毒性（TIAN），以建立最佳实践并发展得出的分级和这种新型毒性的治疗算法。第二个目的侧重于疗效，评估 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渗透性肿瘤中标准射线照相成像的局限性学习辅助MRI放射素学方法来量化肿瘤内的质地变化，并评估是否变化与临床结果相关，我们评估GD2-CART是否诱导CSF细胞的变化 DNA可以对抗肿瘤反应进行快速定量评估。我们的第三个目标是发现目标专注于提高对GD2-CART后与髓样细胞激活相关的生物学的理解我们在临床前模型中观察到的DMG治疗，我们在接受治疗的第一位患者中观察到。我们在这里在患者的GD2-CART后出现CSF髓样细胞的全面单细胞分析参加了研究和临床前模型，以及使用鼠模型进行测试的床头到基础翻译 GD2-CART诱导的CNS髓样细胞膨胀/激活的假设限制了GD2-CART的功效，由皮质类固醇疗法调节，可以通过工程CD47克服这种障碍 GD2-CART中的过表达。