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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：
10412129
负责人：
Richard G. Vile
金额：
$ 18.21万
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 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10412129
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 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 diffuse midline glioma epidermal growth factor receptor VIII expression vector immune stimulant 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