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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.

项目总结