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.

选择最佳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。间变性淋巴瘤激酶 （ALK） 受体由大多数神经母细胞瘤表达，而在大多数正常组织中几乎不存在。ALK 是神经母细胞瘤中的致癌驱动因素，ALK 抑制剂显示出有前景的临床活性。在这里，我们描述了 ALK 的发展。CAR-T 细胞在对抗神经母细胞瘤的单药治疗中显示出有效的疗效，具有高 ALK 表达且无毒性。对于 ALK 表达低的神经母细胞瘤，与 ALK 抑制剂联合使用可特异性增强 ALK。CAR-T 细胞，但不是 GD2。CAR-T 细胞。从机制上讲，ALK 抑制剂会损害肿瘤生长并上调 ALK 的表达，从而促进 ALK 的活性。CAR-T 细胞对抗神经母细胞瘤。因此，虽然既不是 ALK 抑制剂也不是 ALK.CAR-T 细胞可能足以作为低 ALK 密度神经母细胞瘤的单一疗法，它们的组合特异性地增强了治疗效果。