Targeting and Delivering CAR-Ts in Glioblastoma

项目摘要 嵌合抗原受体重定向过继转移的T细胞的显著临床活性 针对CD19抗原的(CAR)和编码共刺激内域可能改变传统的 B细胞恶性肿瘤的近期治疗。基于CAR-T细胞的治疗策略的研究进展 胶质母细胞瘤(GBM)的患者仍然具有挑战性，因为这种肿瘤表现出不同的表达 靶向肿瘤相关抗原，包含通常不被人类GBM反映的干细胞样细胞 临床前模型中使用的细胞系和形成亲肿瘤和免疫抑制环境。此外, 在GBM中交付CAR-T需要新的方法来确保T细胞到达并停留在 肿瘤环境。我们已经鉴定了硫酸软骨素蛋白多糖4(CSPG4)是高度相关的GBM- 相关抗原用于靶向免疫治疗，因为它在超过68%的 原发的基底膜样本，正常脑中不存在。CSPG4在人干细胞样基底膜细胞中高表达 如基底膜源性神经球(GBM-NS)，其表达是由释放的肿瘤坏死因子α诱导的 肿瘤周围的炎性细胞。我们的数据表明，CSPG4.CAR-ts能够控制细胞的生长 GBM-NS的体外和体内实验表明，该策略可能具有重大的临床影响。然而， CSPG4.CAR-ts虽然有效，但并不能始终如一地根除GBM-NS。我们的主要假设是 要根除GBM-NS，我们需要进一步改造CSPG4CAR-ts来克服检查点抑制。我们 还设计了一种可注射的水凝胶，可以确保注射的CAR-T逐渐和更长时间地释放 肿瘤内。该提案产生的信息将有助于设计最优的汽车 根除GBM。

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.