权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Overcoming tumor heterogeneity in glioblastoma with multi-targeted CAR T cells secreting bispecific antibodies

利用分泌双特异性抗体的多靶点 CAR T 细胞克服胶质母细胞瘤的肿瘤异质性

基本信息

批准号：
10685596
负责人：
Marcela Valderrama Maus
金额：
$ 54.52万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-20 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10685596
关键词：
Address Adoptive Immunotherapy Antibodies Antigen Presentation Antigens B lymphoid malignancy Biological Assay Bispecific Antibodies Brain Brain Neoplasms Bulky Disease Bypass CD19 gene CTLA4 gene Cell secretion Cells Central Nervous System Clinical Clinical Trials Data Disease Disease Progression Drug Kinetics Engineering Epidermal Growth Factor Receptor Epitope spreading FDA approved Genetic Engineering Glioblastoma Glioma Goals Heterogeneity Human Immune Immunosuppression Immunotherapy Infusion procedures Intracranial Neoplasms Intravenous infusion procedures Investigational New Drug Application Lung Malignant - descriptor Malignant Neoplasms Mediating Membrane Proteins Modeling Mutation Normal tissue morphology Oncogenic PD-1/PD-L1 PDL1 pathway Patients Penetration Peripheral Pharmaceutical Preparations Phase I Clinical Trials Primary Brain Neoplasms Recurrence Regulatory T-Lymphocyte Role Route Sampling Site Skin Solid Neoplasm Surface Antigens T cell infiltration T-Lymphocyte T-cell receptor repertoire Testing Toxic effect Toxicity Tests Tumor Escape Work Xenograft Model bi-specific T cell engager blood-brain barrier crossing blood-brain barrier penetration brain tissue chimeric antigen receptor chimeric antigen receptor T cells clinical development clinical efficacy cytotoxic design effector T cell engineered T cells epidermal growth factor receptor VIII first-in-human high dimensionality immune checkpoint blockade immunoengineering leukemia/lymphoma model design mouse model neoplastic cell novel patient derived xenograft model personalized immunotherapy preclinical study receptor response side effect trafficking tumor tumor heterogeneity tumor microenvironment tumor progression

项目摘要

PROJECT SUMMARY Glioblastoma (GBM) is uniformly lethal and is the most common malignant primary brain tumor. Immunotherapy promises a precise approach, and the hope of durability. One way to deliver precision immunotherapy is with genetically-engineered T cells designed to express a target-specific chimeric antigen receptor, or CAR. In 2017, CAR T cells targeting CD19 were approved by the FDA for B cell malignancies, and several CARs targeting GBM have been described recently. We have developed CARs that target the EGFRvIII tumor mutation, and demonstrated their activity in preclinical studies and in a first-in-human clinical trial. We found that peripheral infusion of CART-EGFRvIII cells was safe and led to elimination of EGFRvIII-expressing glioma cells in patients. However, despite CART-EGFRvIII trafficking to intracranial tumors and targeting of EGFRvIII, the patients ultimately had outgrowth of EGFRvIII-negative disease and tumor progression. Thus, while the CAR T cell platform certainly holds great promise, a critical barrier to clinical impact for brain tumors is targeting a single antigen in an inherently heterogeneous disease. In addition, our study also demonstrated an adaptive increase in immunosuppression within the tumor microenvironment; specifically, the endogenous T cell infiltrate increased in the tumor, but consisted largely of immune-suppressive regulatory T cells (TRegs), rather than effector T cells reflective of antitumor epitope spreading. To simultaneously address antigenic heterogeneity and promote local antitumor activity in GBM, we have now modified CART-EGFRvIII to secrete bispecific antibodies known as bispecific T cell engagers (BiTEs) against wild-type EGFR, which is not expressed in the normal brain but is nearly always expressed in GBM. Delivering BiTES to the brain using T cells as carriers is also attractive because antibodies do not effectively cross the blood-brain barrier. The overall goal of this work is to develop a safe and effective immunotherapy for patients with GBM. We test the hypothesis that anti- EGFRvIII CAR T cells designed to secrete anti-EGFR BiTEs (CAR-BiTE) will lead to potent and durable responses in models of heterogeneous GBM. We will test their mechanism of action by quantifying secretion of BiTEs and systematically testing the role of bystander T cells (Aim 1). Next, we will determine the optimal route of administration of CAR-BiTE products, and the pharmacokinetics and biostribution of these two-in-one active "drugs” (Aim 2). These data are expected to lead to an Investigational New Drug (IND) application and Phase I clinical trial of CART-vIII/BiTE-EGFR in patients with recurrent glioblastoma. Finally, CAR-BiTEs represent a platform that can target multiple combinations of antigens. In Aim 3 we will identify targetable antigens in primary glioma samples and test CAR-BiTEs targeting three or more antigens.

项目总结