小柯机器人

美国波士顿儿童医院Roberto Chiarle团队发现，ALK抑制剂可增加ALK表达并使神经母细胞瘤细胞对ALK.CAR-T细胞敏感。这一研究成果于2023年11月30日在线发表在国际学术期刊《癌细胞》上。

研究人员表示，选择最佳肿瘤抗原是嵌合抗原受体（CAR）T细胞治疗血液恶性肿瘤和实体瘤取得成功的关键。大多数神经母细胞瘤都表达ALK（anaplasticlymphoma kinase）受体，而大多数正常组织几乎不表达这种受体。ALK是神经母细胞瘤的致癌驱动因子，ALK抑制剂显示出良好的临床活性。

研究人员介绍了ALK.CAR-T细胞的开发情况，这种细胞在单药治疗ALK高表达的神经母细胞瘤中显示出强大的疗效，且无毒性。对于低ALK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细胞的疗效，但不能增强GD2.CAR-T细胞的疗效。从机理上讲，ALK抑制剂会影响肿瘤生长并上调ALK的表达，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抑制剂和ALK.CAR-T细胞可能都不足以作为单一疗法，但它们的联合用药会特异性增强疗效。

附：英文原文

Title: ALK inhibitors increase ALK expression and sensitize neuroblastoma cells to ALK.CAR-T cells

Author: Elisa Bergaggio, Wei-Tien Tai, Andrea Aroldi, Carmen Mecca, Elisa Landoni, Manuel Nüesch, Ines Mota, Jasna Metovic, Luca Molinaro, Leyuan Ma, Diego Alvarado, Chiara Ambrogio, Claudia Voena, Rafael B. Blasco, Tongqing Li, Daryl Klein, Darrell J. Irvine, Mauro Papotti, Barbara Savoldo, Gianpietro Dotti, Roberto Chiarle

Issue&Volume: 2023-11-30

Abstract: Selection of the best tumor antigen is critical for the therapeutic success of chimericantigen receptor (CAR) T cells in hematologic malignancies and solid tumors. The anaplasticlymphoma kinase (ALK) receptor is expressed by most neuroblastomas while virtuallyabsent in most normal tissues. ALK is an oncogenic driver in neuroblastoma and ALKinhibitors show promising clinical activity. Here, we describe the development ofALK.CAR-T cells that show potent efficacy in monotherapy against neuroblastoma withhigh ALK expression without toxicity. For neuroblastoma with low ALK expression, combinationwith ALK inhibitors specifically potentiates ALK.CAR-T cells but not GD2.CAR-T cells.Mechanistically, ALK inhibitors impair tumor growth and upregulate the expressionof 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 asmonotherapy in neuroblastoma with low ALK density, their combination specificallyenhances therapeutic efficacy.

DOI: 10.1016/j.ccell.2023.11.004

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(23)00395-1

Cancer Cell：《癌细胞》，创刊于2002年。隶属于细胞出版社，最新IF：38.585
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