Targeting GD2-positive glioblastoma by chimeric antigen receptor empowered mesenchymal progenitors
Targeting GD2-positive glioblastoma by chimeric antigen receptor empowered mesenchymal progenitors
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DOI：
10.1038/s41417-018-0062-x
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发表时间：
2020-08-01
影响因子：
6.4
通讯作者：
Dominici, Massimo
中科院分区：
文献类型：
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作者：
Golinelli, Giulia;Grisendi, Giulia;Dominici, Massimo
通过携带抗癌分子的遗传修饰的间充质基质/干细胞（MSC）的肿瘤靶向是一种有前途的基于细胞的策略。我们先前表明，促凋亡剂肿瘤坏死因子相关的凋亡诱导配体（TRAIL）可以成功地由MSC交付到癌症部位。虽然TRAIL与其受体之间的相互作用是明确的，但更模糊的是MSC选择性靶向肿瘤及其抗原的方式。几种神经外胚层来源的肿瘤，包括胶质母细胞瘤（GBM）、肉瘤和神经母细胞瘤，表达高水平的肿瘤相关抗原GD 2。我们已经通过嵌合抗原受体（CAR）-T细胞方法对抗神经母细胞瘤来挑战这种细胞表面二唾液酸神经节苷脂。为了最大化MSC递送TRAIL的治疗特性，我们在这里最初开发了一种双功能策略，其中TRAIL由MSC递送，所述MSC也用抗GD 2 CAR（GD 2 tCAR）的截短形式进行基因修饰以介导GD 2阳性肿瘤的免疫选择性识别。这些双功能MSC表达高水平的TRAIL和GD 2 tCAR，这与针对GD 2阳性GBM细胞的强大抗肿瘤活性相关。最重要的是，这种双功能细胞的靶向潜力增强了抗癌作用。总的来说，我们的研究结果表明，截短的抗GD 2 CAR可能是一种强大的新工具，可以将携带TRAIL的MSC重定向到表达GD 2的肿瘤。这种基于亲和力的双重靶向有望将联合收割机位点特异性和延长MSC在表达GD 2的肿瘤中的保留相结合，从而为仍然无法治愈的癌症提供更有效的TRAIL递送。
Tumor targeting by genetically modified mesenchymal stromal/stem cells (MSCs) carrying anti-cancer molecules represents a promising cell-based strategy. We previously showed that the pro-apoptotic agent tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can be successfully delivered by MSCs to cancer sites. While the interaction between TRAIL and its receptors is clear, more obscure is the way in which MSCs can selectively target tumors and their antigens. Several neuroectoderm-derived neoplasms, including glioblastoma (GBM), sarcomas, and neuroblastoma, express high levels of the tumor-associated antigen GD2. We have already challenged this cell surface disialoganglioside by a chimeric antigen receptor (CAR)-T cell approach against neuroblastoma. With the intent to maximize the therapeutic profile of MSCs delivering TRAIL, we here originally developed a bi-functional strategy where TRAIL is delivered by MSCs that are also gene modified with the truncated form of the anti-GD2 CAR (GD2 tCAR) to mediate an immunoselective recognition of GD2-positive tumors. These bi-functional MSCs expressed high levels of TRAIL and GD2 tCAR associated with a robust anti-tumor activity against GD2-positive GBM cells. Most importantly, the anti-cancer action was reinforced by the enhanced targeting potential of such bi-functional cells. Collectively, our results suggest that a truncated anti-GD2 CAR might be a powerful new tool to redirect MSCs carrying TRAIL against GD2-expressing tumors. This affinity-based dual targeting holds the promise to combine site-specific and prolonged retention of MSCs in GD2-expressing tumors, thereby providing a more effective delivery of TRAIL for still incurable cancers.