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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.

项目总结尽管嵌合抗原受体(CAR)T细胞在血液学方面取得了显著的成功，许多实体肿瘤适应症的真正肿瘤特异性抗原的鉴定限制了广泛的翻译。二已考虑作为弥漫性中线胶质瘤H3 K27M突变型肿瘤(以前为弥漫性固有肿瘤)的靶点桥脑胶质瘤(DIPG)，然而，由于两者都不局限于肿瘤组织，安全性问题存在靶标上、肿瘤外的毒性。此外，辅助治疗意在增强CAR T功能克服与实体瘤相关的一系列免疫抑制机制微环境也有可能使问题恶化。我们小组已经进行了广泛的溶瘤病毒的临床前特征，并已证明它们是一种高效的用于治疗癌症的免疫治疗剂。我们建议利用∆24的肿瘤趋向性溶瘤腺病毒与CD40L一起传递CAR靶点。我们的初步数据显示，溶瘤作为一种单一疗法，Ad∆24-CD40L在GL261胶质瘤模型中提供了显著的治疗优势。此外，可以在针对皮下组织的概念验证组合中加强CD19 CAR T治疗 B16-CD19肿瘤。这项提议的目标是开发一种建立在直接治疗基础上的双重治疗方法病毒介导的肿瘤细胞溶瘤和CAR T细胞溶解，增强CAR T细胞募集/激活炎症，更重要的是，CD40L介导的内源性抗原提呈细胞，B细胞的动员和T细胞。我们将设计一种溶瘤载体，利用大肠杆菌DHFR传递可滴定水平的CD40L 不稳定结构域，以及细胞内截短的信号转导死亡的EGFRvIII分子结合安全性测试的EGFRvIII CAR T细胞(Aim1)。OV-CAR T的安全性和有效性该方法将在DIPG的基因工程免疫活性模型(AIM 2)中进行评估。这个项目有望为CD40L如何动员内源性B细胞和T细胞反应提供新的见解并支持CAR T疗法。总之，我们希望利用设计的溶瘤病毒的特性来更广泛地允许在实体肿瘤中使用CAR T细胞疗法，特别是应用现有的安全性测试免疫疗法，以满足毁灭性和迫切的临床需求。