文章目录

嵌合抗原受体增强间充质祖细胞靶向GD2阳性胶质母细胞瘤

Targeting GD2-positive glioblastoma by chimeric antigen receptor empowered mesenchymal progenitors

原文发布日期：2018-11-22

英文摘要：

摘要翻译：

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嵌合抗原受体增强间充质祖细胞靶向GD2阳性胶质母细胞瘤

Targeting GD2-positive glioblastoma by chimeric antigen receptor empowered mesenchymal progenitors

原文发布日期：2018-11-22

英文摘要：

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.

摘要翻译：

利用携带抗癌分子的基因修饰间充质基质/干细胞（MSCs）靶向肿瘤是一种具有前景的细胞治疗策略。我们前期研究表明，促凋亡因子肿瘤坏死因子相关凋亡诱导配体（TRAIL）可通过MSCs成功递送至癌症病灶。虽然TRAIL与其受体的相互作用机制明确，但MSCs选择性靶向肿瘤及其抗原的方式仍不甚清晰。神经外胚层来源的多种肿瘤（包括胶质母细胞瘤、肉瘤和神经母细胞瘤）高表达肿瘤相关抗原GD2。我们曾通过嵌合抗原受体（CAR）-T细胞技术靶向神经母细胞瘤表面的这种双唾液酸神经节苷脂。为最大化提升递送TRAIL的MSCs的治疗潜力，本研究创新性地开发了双功能策略：通过基因修饰使MSCs表达截短型抗GD2 CAR（GD2 tCAR），在递送TRAIL的同时介导对GD2阳性肿瘤的免疫选择性识别。这类双功能MSCs能高表达TRAIL和GD2 tCAR，并对GD2阳性胶质母细胞瘤细胞展现出显著抗肿瘤活性。最重要的是，其增强的靶向能力进一步强化了抗癌作用。综上表明，截短型抗GD2 CAR或将成为引导携带TRAIL的MSCs靶向GD2表达肿瘤的新型有力工具。这种基于亲和力的双靶向策略有望实现MSCs在GD2表达肿瘤中的位点特异性滞留和 prolonged 滞留时间，从而为目前仍无法治愈的癌症提供更有效的TRAIL递送方案。