Targeting and Delivering CAR-Ts in Glioblastoma

在胶质母细胞瘤中靶向和递送 CAR-T

• 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
• 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

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 在不久的将来治疗B细胞恶性肿瘤。基于 CAR-T 细胞的治疗策略的开发 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 用于临床前模型并塑造促肿瘤和免疫抑制环境的细胞系。此外， 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 肿瘤环境。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 原发 GBM 样本而不是正常大脑中的样本。 CSPG4 在人类干细胞（如 GBM 细胞）中高度表达 例如GBM源性神经球（GBM-NS），其表达是由GBM释放的TNFα诱导的 肿瘤周围的炎症细胞。我们的数据表明 CSPG4.CAR-Ts 可以控制 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。然而， 尽管有效，CSPG4.CAR-T 并不能始终如一地根除 GBM-NS。我们的主要假设是 为了根除 GBM-NS，我们需要进一步设计 CSPG4.CAR-T 来克服检查点抑制。我们 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 瘤内。该提案生成的信息将有助于设计最佳的 CAR-T 根除GBM。