Abstract 50: ALK inhibitors increase ALK expression and sensitize neuroblastoma cells to ALK.CAR-T cells

Abstract Neuroblastoma is the most common extracranial solid tumor of childhood, with limited success in treating refractory or relapsed cases using current therapies. Chimeric antigen receptor (CAR) T cell therapy targeting GD2 has shown promise in neuroblastoma treatment, but relapses are associated with loss of antigen expression. The selection of the best tumor antigen is critical for the therapeutic success of 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. All these features make ALK an attractive target for CAR-T cell therapy. We developed 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. In neuroblastoma cell lines and in a patient-derived xenograft (PDX), the combination of ALK inhibitors and ALK. CAR-T cells significantly reduced tumor growth and extended mice survival. 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. These findings provide insights into the potential of ALK. CAR-T cells as a novel therapeutic strategy for neuroblastoma. A Phase I clinical trial to test ALK. CAR-T cells in combination with ALK TKIs in children with refractory/relapsed neuroblastoma is being implemented based on these results. Citation Format: 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 Savolodo, Gianpietro Dotti, Roberto Chiarle. ALK inhibitors increase ALK expression and sensitize neuroblastoma cells to ALK. CAR-T cells abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 50.