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 细胞在血液恶性肿瘤和实体瘤中的治疗成功至关重要。大多数神经母细胞瘤表达间变性淋巴瘤激酶 (ALK) 受体，而大多数正常组织中几乎不表达。 ALK 是神经母细胞瘤的致癌驱动因素，ALK 抑制剂显示出有希望的临床活性。在这里，我们描述了 ALK.CAR-T 细胞的开发，该细胞在针对高 ALK 表达的神经母细胞瘤的单一疗法中显示出强大的功效，且无毒性。对于 ALK 表达低的神经母细胞瘤，与 ALK 抑制剂组合可特异性增强 ALK.CAR-T 细胞，但不能增强 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.CAR-T 细胞对抗神经母细胞瘤的活性。因此，虽然 ALK 抑制剂和 ALK.CAR-T 细胞都可能不足以作为 ALK 密度低的神经母细胞瘤的单一疗法，但它们的组合可以特异性增强治疗效果。