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.

项目摘要胶质母细胞瘤（GBM）是统一致死的，是最常见的恶性原发性脑肿瘤。免疫疗法承诺采用精确的方法和耐用性的希望。交付精度的一种方法免疫疗法的遗传工程T细胞设计用于表达靶标特异性嵌合抗原接收器或汽车。 2017年，FDA批准了针对CD19的CAR T细胞用于B细胞Malignancys，并且最近已经描述了一些针对GBM的汽车。我们已经开发了针对EGFRVIII的汽车肿瘤突变，并在临床前研究和人类临床试验中证明了它们的活性。发现CART-EGFRVIII细胞的周围输注是安全的，并导致消除EGFRVIII-Exptressing 患者的神经瘤细胞。然而，尽管卡特 - egfrviii贩运颅内肿瘤和靶向 EGFRVIII，患者最终的EGFRVIII-阴性疾病和肿瘤进展生长。那，虽然汽车T细胞平台肯定具有巨大的希望，但对脑肿瘤临床影响的关键障碍是靶向固有异质性疾病中的单个抗原。此外，我们的研究还证明了肿瘤微环境中免疫抑制的适应性增加；具体而言，内源性T细胞肿瘤中的浸润增加，但持续地抑制了免疫抑制的调节T细胞（Treg），而是而不是反射抗肿瘤表位扩散的效应T细胞。同时解决抗原异质性并促进GBM中的局部抗肿瘤活性，我们现在已经修改了Cart-Egfrviii秘密双特异性抗体被称为双特异性T细胞探测器（咬伤），抗野生型EGFR，该抗体未在正常的大脑，但几乎总是在GBM中表达。用T细胞作为载体将咬伤向大脑咬伤是也很有吸引力，因为抗体不能有效地越过血脑屏障。这项工作的总体目标是为GBM患者开发安全有效的免疫疗法。我们检验了一个假说，抗 EGFRVIII CAR T细胞设计为秘密抗EGFR叮咬（CAR-BITE）将导致潜在耐用异质GBM模型中的响应。我们将通过量化分泌的分泌来测试其行动机理叮咬和系统地测试旁观者T细胞的作用（AIM 1）。接下来，我们将确定最佳路线驾驶汽车产品的给药，以及这些两合一活动的药代动力学和生物 “药物”（AIM 2）。这些数据有望导致研究新药（IND）应用和I期 CART-VIII/咬合 - EGFR在复发性胶质母细胞瘤患者中的临床试验。最后，卡车代表可以针对多种抗原组合的平台。在AIM 3中，我们将确定主要的抗原胶质瘤样品和靶标的靶向三个或更多抗原的摄影作品。