Novel Strategies to Treat Diffuse Midline Glioma with CAR T Cell Therapy

利用 CAR T 细胞疗法治疗弥漫性中线胶质瘤的新策略

基本信息

批准号：
10284722
负责人：
Richard G. Vile
金额：
$ 22.3万
依托单位：
MAYO CLINIC ROCHESTER
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：
2021-06-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10284722
关键词：
Adenovirus Vector Affinity Anatomy Antigen Presentation Antigen Receptors Antigen Targeting Antigen-Presenting Cells Antigens B-Lymphocytes Brain Neoplasms Brain Stem CAR T cell therapy CD19 gene CD276 gene CD80 gene Cells Chemosensitization Clinical Combined Modality Therapy Complement Cytolysis DHFR gene Data Dendritic cell activation Diffuse Diffuse intrinsic pontine glioma Disease Engineering Escherichia coli Genetic Engineering Glioma Goals H3 K27M mutation Hematology Immune Immune system Immunocompetent Immunotherapeutic agent Immunotherapy Inflammation Interleukin-12 Licensing Location Mediating Modeling Normal tissue morphology Oncolytic Oncolytic viruses Outcome Patients Production Property Reporting Research Project Grants Safety Signal Transduction Solid Neoplasm Stimulus T cell response T-Lymphocyte TNFRSF5 gene TNFSF5 gene Technology Testing Therapeutic Therapeutic Effect Tissues Toxic effect Translations Tropism Tumor Antigens Up-Regulation Viral Virus Virus Activation cancer therapy chimeric antigen receptor chimeric antigen receptor T cells combinatorial cytokine epidermal growth factor receptor VIII expression vector insight melanoma neoplastic neoplastic cell novel novel strategies oncolysis oncolytic adenovirus oncolytic vector pre-clinical recruit research clinical testing response safety testing subcutaneous tumor tumor microenvironment vector

项目摘要

PROJECT SUMMARY Although chimeric antigen receptor (CAR) T cells have been remarkably successful in the hematologic setting, identification of truly tumor specific antigens for many solid tumor indications has limited broad translation. Two targets have been considered for Diffuse Midline Glioma H3 K27M-mutant tumors (previously Diffuse Intrinsic Pontine Glioma (DIPG)), however as neither are exclusively restricted to neoplastic tissue, safety concerns exist with respect to on-target, off-tumor toxicity. Moreover, ancillary treatment meant to boost CAR T function to overcome a constellation of immune suppressive mechanisms associated with the solid tumor microenvironment also has the potential to exacerbate the problem. Our group has conducted extensive preclinical characterization of oncolytic viruses and has demonstrated them to be a highly effective immunotherapeutic agents for the treatment of cancer. We propose to leverage the tumor tropism of ∆24 oncolytic adenovirus to deliver a CAR target along with CD40L. Our preliminary data indicates that oncolytic Ad∆24-CD40L provides a significant therapeutic advantage in a GL261 glioma model as a monotherapy, and further, can potentiate CD19 CAR T therapy in a proof of concept combination setting against subcutaneous B16-CD19 tumors. The goal of this proposal is to develop a dual therapy approach which builds on direct tumor cell viral oncolysis and CAR T cytolysis, enhanced CAR T cell recruitment/activation by virus-mediated inflammation, and importantly, CD40L-mediated mobilization of endogenous antigen presenting cells, B cells and T cells. We will engineer an oncolytic vector to deliver titratable levels of CD40L using the E. coli DHFR destabilizing domain, and an intracellularly truncated signaling-dead EGFRvIII molecule to be used in conjunction with safety tested EGFRvIII CAR T cells (Aim1). The safety and efficacy of the OV-CAR T approach will be evaluated in a genetically engineered immunocompetent model of DIPG (Aim 2). This project is expected to provide novel insight into how CD40L can mobilize an endogenous B cell and T cell response and support CAR T therapy. Together, we hope to capitalize on the properties of designer oncolytic viruses to more broadly enable the use of CAR T cell therapy in solid tumors, and in particular apply existing safety tested immunotherapies to a devastating and urgent unmet clinical need.

项目摘要尽管嵌合抗原受体（CAR）T细胞在血液学环境中取得了非常成功的成功，但许多实体瘤适应症的真正肿瘤特异性抗原的鉴定具有有限的广泛翻译。二已经考虑了弥漫性中线神经胶质瘤H3 K27M突变肿瘤（以前弥漫性固有）但是，庞蒂氏神经胶质瘤（DIPG）），但是，两者都不仅限于肿瘤组织存在于靶向，肿瘤的毒性。此外，辅助治疗旨在提高汽车t功能要克服与实体瘤相关的免疫抑制机制微环境也有可能加剧问题。我们的小组进行了广泛的溶瘤病毒的临床前表征，并证明它们是高效的用于治疗癌症的免疫治疗剂。我们建议利用∆24的肿瘤向潮流溶瘤腺病毒与CD40L一起提供汽车靶标。我们的初步数据表明溶瘤 ADΔ24-CD40L在GL261神经胶质瘤模型作为单一疗法中提供了显着的热优势，并且此外，在概念验证验证中，可能会在概念验证的情况下对皮下进行CD19 CAR T治疗 B16-CD19肿瘤。该建议的目的是开发一种双重疗法，以直接为基础肿瘤细胞病毒闭塞和CAR T细胞解，病毒介导的CAR T细胞募集/激活增强炎症，重要的是，CD40L介导的内源性抗原呈递细胞的动员B细胞和T细胞。我们将使用大肠杆菌DHFR来设计一种溶瘤载体，以提供CD40L的钛水平不稳定的域，并在细胞内截断的信号dead egfrviii分子用于与安全测试的EGFRVIII CAR T细胞的联系（AIM1）。椭圆车T的安全性和易度性方法将在dipg的一般工程化的免疫能力模型中进行评估（AIM 2）。这个项目预计将提供有关CD40L如何动员内源B细胞和T细胞反应的新见解并支持汽车治疗。我们一起，我们希望将设计师的溶瘤病毒的特性大写更广泛地可以在实体瘤中使用CAR T细胞疗法，特别是应用现有安全性测试了对毁灭性和紧急未满足的临床需求的免疫疗法。