Targeting and Delivering CAR-Ts in Glioblastoma

在胶质母细胞瘤中靶向和递送 CAR-T

基本信息

批准号：
9886209
负责人：
Gianpietro Dotti
金额：
$ 16.91万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
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：
2019-04-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9886209
关键词：
Address Animals Antibodies Antigen Targeting Antigens B lymphoid malignancy Biocompatible Materials Brain Brain Neoplasms CD19 Antigens Cell Line Cell surface Cells Characteristics Chondroitin Sulfate Proteoglycan Clinical Clinical Data Clinical Research Data Development Engineering Ensure Environment Formulation Future Glioblastoma Glioma Glycoproteins Growth Hematologic Neoplasms Histologic Human Hydrogels Immune Immunize Immunosuppression Immunotherapy In Situ In Vitro Inflammatory Injectable Integral Membrane Protein Link Mediating Messenger RNA Minority Molecular Nerve Normal tissue morphology Patients Peptides Pericytes Pharmaceutical Preparations Pre-Clinical Model Proteins Proteoglycan Publishing Rattus Reporting Sampling Shapes Site Solid Neoplasm Structure T cell therapy T-Lymphocyte TNF gene Testing Time Translational Research Tumor Antigens Tumor Escape Water Xenograft procedure anti-PD-L1 antitumor effect base biocompatible polymer biodegradable polymer checkpoint inhibition chimeric antigen receptor chimeric antigen receptor T cells conventional therapy design effective therapy human stem cells hydrophilicity improved in vivo leukemia mouse model neoplastic cell novel strategies overexpression programmed cell death ligand 1 response stem-like cell success tumor tumor progression

项目摘要

Project Abstract The remarkable clinical activity of adoptively transferred T cells redirected with a chimeric antigen receptor (CAR) specific for the CD19 antigen and encoding co-stimulatory endodomains may change the conventional treatment of B-cell malignancies in the near future. The development of CAR-T cell-based strategies to treat patients with glioblastoma (GBM) remains challenging because this tumor shows heterogeneous expression of targetable tumor-associated antigens, contains stem-cell-like cells that are not usually mirrored by human GBM cell lines used in preclinical models and shapes pro-tumor and immune suppressive environment. In addition, the delivery of CAR-Ts in GBM requires novel approaches to ensure that T cells reach and stay within the tumor environment. We have identified chondroitin sulphate proteoglycan 4 (CSPG4) as highly relevant GBM- associated antigen for targeted immunotherapy since it is highly and strongly overexpressed in over 68% of primary GBM samples and not in normal brain. CSPG4 is highly expressed by human stem-cell like GBM cells such as GBM-derived neurospheres (GBM-NS), and its expression is induced by TNFα released by inflammatory cells surrounding the tumor. Our data indicate that CSPG4.CAR-Ts can control the growth of GBM-NS in vitro and in vivo indicating that this strategy may have significant clinical impact. However, although effective, CSPG4.CAR-Ts do not consistently eradicate GBM-NS. It is our main hypothesis that to eradicate GBM-NS we need further engineering of CSPG4.CAR-Ts to overcome checkpoint inhibition. We have also devised an injectable hydrogel that may ensure gradual and longer release of CAR-Ts injected intratumor. Information generated by the proposal will be instrumental to design the optimal CAR-Ts to eradicate GBM.

项目摘要嵌合抗原受体重定向的过继转移 T 细胞的显着临床活性特异性针对 CD19 抗原并编码共刺激内域的 (CAR) 可能会改变传统的在不久的将来，开发基于 CAR-T 细胞的治疗策略。胶质母细胞瘤（GBM）患者仍然具有挑战性，因为这种肿瘤表现出异质性表达可靶向的肿瘤相关抗原，包含通常不被人类 GBM 镜像的干细胞样细胞此外，用于临床前模型并塑造促肿瘤和免疫抑制环境的细胞系。 GBM 中 CAR-T 的递送需要新的方法来确保 T 细胞到达并停留在我们已确定硫酸软骨素蛋白聚糖 4 (CSPG4) 与 GBM- 高度相关。相关抗原用于靶向免疫治疗，因为它在超过 68% 的患者中高度强烈过表达 CSPG4 在原代 GBM 样本中而非正常大脑中由人类干细胞（如 GBM 细胞）高度表达。例如GBM源性神经球（GBM-NS），其表达是由GBM释放的TNFα诱导的我们的数据表明 CSPG4.CAR-T 可以控制肿瘤周围的炎症细胞的生长。 GBM-NS 的体外和体内实验表明该策略可能具有显着的临床影响。尽管有效，CSPG4.CAR-T 并不能始终如一地根除 GBM-NS，这是我们的主要假设。根除 GBM-NS，我们需要进一步设计 CSPG4.CAR-T 来克服检查点抑制。还设计了一种可注射水凝胶，可以确保注射的 CAR-T 逐渐且更长时间地释放该提案产生的信息将有助于设计最佳的 CAR-T。根除GBM。