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：
10469337
负责人：
Marcela Valderrama Maus
金额：
$ 55.64万
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/10469337
关键词：
Address Adoptive Immunotherapy Antibodies Antigen Presentation Antigen Targeting Antigens B lymphoid malignancy B-Lymphocytes Biological Assay Bispecific Antibodies Bite Blood - brain barrier anatomy Brain Brain Neoplasms Bulky Disease Bypass CD19 gene CTLA4 gene Cells 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 Intravenous infusion procedures Investigational New Drug Application Lead 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-Lymphocyte T-cell receptor repertoire Testing Toxic effect Toxicity Tests Tumor Escape Work Xenograft Model base bi-specific T cell engager 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 pre-clinical 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.

项目概要胶质母细胞瘤（GBM）均具有致命性，是最常见的恶性原发性脑肿瘤。免疫疗法有望提供一种精确的方法，并有望实现持久性。免疫疗法是利用基因工程 T 细胞来表达特定靶点的嵌合抗原 2017 年，FDA 批准靶向 CD19 的 CAR T 细胞用于治疗 B 细胞恶性肿瘤。最近描述了几种针对 GBM 的 CAR，我们开发了针对 EGFRvIII 的 CAR。肿瘤突变，并在临床前研究和首次人体临床试验中证明了它们的活性。发现外周输注 CART-EGFRvIII 细胞是安全的，并且可以消除表达 EGFRvIII 的细胞然而，尽管 CART-EGFRvIII 转运至颅内肿瘤并靶向 EGFRvIII，患者最终出现 EGFRvIII 阴性疾病和肿瘤进展。虽然 CAR T 细胞平台无疑前景广阔，但影响脑肿瘤临床影响的一个关键障碍是此外，我们的研究还证明了针对固有异质性疾病的单一抗原。肿瘤微环境中免疫抑制的适应性增加；特别是内源性 T 细胞肿瘤中的浸润增加，但主要是免疫抑制性调节性 T 细胞 (TReg)，而不是比效应 T 细胞反映抗肿瘤表位扩散，同时解决抗原异质性。并促进 GBM 的局部抗肿瘤活性，我们现在已经修改了 CART-EGFRvIII 以分泌双特异性针对野生型 EGFR 的称为双特异性 T 细胞接合器 (BiTE) 的抗体，野生型 EGFR 不表达于正常大脑，但几乎总是在 GBM 中表达，使用 T 细胞作为载体将 BiTES 递送至大脑。也很有吸引力，因为抗体不能有效地穿过血脑屏障这项工作的总体目标。我们的目标是为 GBM 患者开发一种安全有效的免疫疗法。旨在分泌抗 EGFR BiTE (CAR-BiTE) 的 EGFRvIII CAR T 细胞将带来有效且持久的治疗我们将通过量化 GBM 的分泌来测试其作用机制。 BiTE 和系统测试旁观者 T 细胞的作用（目标 1）接下来，我们将确定最佳路线。 CAR-BiTE 产品的给药方式，以及这些二合一活性物质的药代动力学和生物分布 “药物”（目标 2）预计将导致新药研究 (IND) 申请和 I 期临床试验。最后，CAR-BiTE 代表了复发性胶质母细胞瘤患者的 CART-vIII/BiTE-EGFR 临床试验。在目标 3 中，我们将鉴定初级中的可靶向抗原。神经胶质瘤样本并测试针对三种或更多抗原的 CAR-BiTE。