Center for Cell and Gene Therapy, Baylor College of Medicine, The Methodist Hospital and Texas Children's Hospital, Houston, TX, USA.
J Immunother. 2010 Oct;33(8):780-8. doi: 10.1097/CJI.0b013e3181ee6675.
For adoptive T-cell therapy to be effective against solid tumors, tumor-specific T cells must be able to migrate to the tumor site. One requirement for efficient migration is that the effector cells express chemokine receptors that match the chemokines produced either by tumor or tumor-associated cells. In this study, we investigated whether the tumor trafficking of activated T cells (ATCs) bearing a chimeric antigen receptor specific for the tumor antigen GD2 (GD2-CAR) could be enhanced by forced coexpression of the chemokine receptor CCR2b, as this receptor directs migration toward CCL2, a chemokine produced by many tumors, including neuroblastoma. Neuroblastoma cell lines (SK-N-SH and SK-N-AS) and primary tumor cells isolated from 6 patients all secreted high levels of CCL2, but GD2-CAR transduced ATCs lacked expression of CCR2 (<5%) and migrated poorly to recombinant CCL2 or tumor supernatants. After retroviral transduction, however, ATCs expressed high levels of CCR2b (>60%) and migrated well in vitro. We expressed firefly luciferase in CCR2b-expressing ATCs and observed improved homing (>10-fold) to CCL2-secreting neuroblastoma compared with CCR2-negative ATCs. As a result, ATCs co-modified with both CCR2b and GD2-CAR had greater antitumor activity in vivo.
为了使过继性 T 细胞疗法对实体瘤有效，肿瘤特异性 T 细胞必须能够迁移到肿瘤部位。有效迁移的一个要求是效应细胞表达趋化因子受体，这些受体与肿瘤或肿瘤相关细胞产生的趋化因子相匹配。在这项研究中，我们研究了是否可以通过强制共表达趋化因子受体 CCR2b 来增强表达针对肿瘤抗原 GD2 的嵌合抗原受体的激活 T 细胞 (ATC) 的肿瘤归巢，因为该受体指导向 CCL2 的迁移，CCL2 是许多肿瘤包括神经母细胞瘤产生的趋化因子。神经母细胞瘤细胞系 (SK-N-SH 和 SK-N-AS) 和从 6 名患者分离的原代肿瘤细胞均分泌高水平的 CCL2，但转导 GD2-CAR 的 ATC 缺乏 CCR2 的表达(<5%)，并且向重组 CCL2 或肿瘤上清液迁移能力差。然而，经过逆转录病毒转导后，ATC 表达高水平的 CCR2b(>60%)，并且在体外迁移良好。我们在表达 CCR2b 的 ATC 中表达了萤火虫荧光素酶，并观察到与 CCR2 阴性 ATC 相比，对分泌 CCL2 的神经母细胞瘤的归巢增加了(>10 倍)。结果，同时修饰 CCR2b 和 GD2-CAR 的 ATC 在体内具有更强的抗肿瘤活性。
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