Targeting and Delivering CAR-Ts in Glioblastoma

项目摘要 用嵌合抗原受体重定向的过继转移T细胞的显著临床活性 (CAR)特异于CD 19抗原和编码共刺激胞内域的蛋白质可以改变传统的免疫原性。 B细胞恶性肿瘤的治疗。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，因为这种肿瘤显示出异质性表达， 可靶向的肿瘤相关抗原，包含通常不被人GBM反映的干细胞样细胞 用于临床前模型的细胞系，并形成促肿瘤和免疫抑制环境。此外，本发明还提供了一种方法， CAR-T在GBM中的递送需要新的方法来确保T细胞到达并停留在GBM中。 肿瘤环境我们已经确定硫酸软骨素蛋白聚糖4（CSPG 4）与GBM高度相关。 相关抗原的靶向免疫治疗，因为它是高度和强烈过表达超过68%的 原发性GBM样本，而不是正常大脑。CSPG 4在人干细胞样GBM细胞中高度表达 如GBM衍生的神经球（GBM-NS），其表达由TNFα诱导， 肿瘤周围的炎症细胞我们的数据表明，CSPG 4.CAR-Ts可以控制肿瘤细胞的生长。 GBM-NS在体外和体内的研究表明，这种策略可能具有显着的临床影响。然而，在这方面， 尽管有效，但CSPG 4. CAR-T不能持续根除GBM-NS。我们的主要假设是， 为了根除GBM-NS，我们需要进一步工程化CSPG 4.CAR-Ts以克服检查点抑制。我们 他们还设计了一种可注射的水凝胶，可以确保注射的CAR-T的逐渐和更长时间的释放。 肿瘤内。该提案产生的信息将有助于设计最佳CAR-T， 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.