肿瘤细胞治疗研究
英文原题：ALK inhibitors increase ALK expression and sensitize neuroblastoma cells to ALK.CAR-T cells.
选择最佳的肿瘤抗原对于嵌合抗原受体（CAR）T 细胞在血液系统恶性肿瘤和实体瘤中的治疗成功至关重要。
选择最佳肿瘤抗原对嵌合抗原受体（CAR）T细胞治疗血液系统恶性肿瘤和实体瘤的成功至关重要。间变性淋巴瘤激酶（ALK）受体在多数神经母细胞瘤中表达，而在大多数正常组织中几乎不存在。ALK是神经母细胞瘤的致癌驱动因素，ALK抑制剂显示出令人鼓舞的临床活性。本文介绍了ALK.CAR-T细胞的开发：在ALK高表达的神经母细胞瘤中，单药治疗具有强效疗效且无毒性。对于ALK低表达的神经母细胞瘤，与ALK抑制剂联用可特异性增强ALK.CAR-T细胞作用，但不增强GD2.CAR-T细胞作用。机制上，ALK抑制剂抑制肿瘤生长并上调ALK表达，从而促进ALK.CAR-T细胞对神经母细胞瘤的活性。因此，对于ALK密度较低的神经母细胞瘤，ALK抑制剂或ALK.CAR-T细胞单药可能均不足以奏效，而二者联合可特异性提高治疗效果。
Selection of the best tumor antigen is critical for the therapeutic success of chimeric antigen receptor (CAR) T cells in hematologic malignancies and solid tumors. The anaplastic lymphoma kinase (ALK) receptor is expressed by most neuroblastomas while virtually absent in most normal tissues. ALK is an oncogenic driver in neuroblastoma and ALK inhibitors show promising clinical activity. Here, we describe the development of ALK.CAR-T cells that show potent efficacy in monotherapy against neuroblastoma with high ALK expression without toxicity. For neuroblastoma with low ALK expression, combination with ALK inhibitors specifically potentiates ALK.CAR-T cells but not GD2.CAR-T cells. Mechanistically, ALK inhibitors impair tumor growth and upregulate the expression of ALK, thereby facilitating the activity of ALK.CAR-T cells against neuroblastoma. Thus, while neither ALK inhibitors nor ALK.CAR-T cells will likely be sufficient as monotherapy in neuroblastoma with low ALK density, their combination specifically enhances therapeutic efficacy.
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