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Ref Type Journal Article
PMID (38039964)
Authors Bergaggio E, Tai WT, Aroldi A, Mecca C, Landoni E, Nüesch M, Mota I, Metovic J, Molinaro L, Ma L, Alvarado D, Ambrogio C, Voena C, Blasco RB, Li T, Klein D, Irvine DJ, Papotti M, Savoldo B, Dotti G, Chiarle R
Title ALK inhibitors increase ALK expression and sensitize neuroblastoma cells to ALK.CAR-T cells.
Journal Vol Issue Date Pages Journal Short Title
Cancer cell 41 12 2023 Dec 11 2100-2116.e10 Cancer Cell
URL
Abstract Text 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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
hALK.CAR T cells hALK.CAR T cells 4 1
Drug Name Trade Name Synonyms Drug Classes Drug Description
hALK.CAR T cells hALK.CAR T cells are T-lymphocytes engineered to express a chimeric antigen receptor (CAR) targeting ALK linked to the CD8 alpha hinge and transmembrane domain, CD28 costimulatory domain, and CD3zeta signaling domain, which potentially induces cytoxicity against tumor cells with high Alk expression (PMID: 38039964).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ALK amp neuroblastoma sensitive hALK.CAR T cells Preclinical - Cell line xenograft Actionable In a preclinical study, co-culture with hALK.CAR T cells induced killing of neuroblastoma cells with ALK amplification in culture and inhibited tumor growth and improved tumor-free survival in a cell line xenograft model (PMID: 38039964). 38039964
ALK R1275Q neuroblastoma sensitive hALK.CAR T cells Preclinical - Cell culture Actionable In a preclinical study, co-culture with hALK.CAR T cells induced killing of neuroblastoma cells harboring ALK R1275Q in culture (PMID: 38039964). 38039964
ALK F1245C neuroblastoma sensitive hALK.CAR T cells Preclinical - Patient cell culture Actionable In a preclinical study, co-culture with hALK.CAR T cells induced killing of cells derived from a patient-derived xenograft (PDX) model of neuroblastoma harboring ALK F1245C in culture (PMID: 38039964). 38039964
ALK R1275Q neuroblastoma sensitive Ceritinib + hALK.CAR T cells Preclinical - Cell culture Actionable In a preclinical study, Zykadia (ceritinib) treatment resulted in increased death of neuroblastoma cells harboring ALK R1275Q when co-cultured with hALK.CAR T cells compared to control CAR-T cells in culture (PMID: 38039964). 38039964
ALK F1174L neuroblastoma sensitive hALK.CAR T cells Preclinical - Cell culture Actionable In a preclinical study, co-culture with hALK.CAR T cells induced killing of neuroblastoma cells harboring ALK F1174L in culture (PMID: 38039964). 38039964
ALK F1174L neuroblastoma sensitive Ceritinib + hALK.CAR T cells Preclinical - Cell culture Actionable In a preclinical study, Zykadia (ceritinib) treatment resulted in increased death of neuroblastoma cells harboring ALK F1174L when co-cultured with hALK.CAR T cells compared to control CAR-T cells in culture (PMID: 38039964). 38039964
ALK F1174L neuroblastoma sensitive hALK.CAR T cells + Lorlatinib Preclinical - Cell line xenograft Actionable In a preclinical study, Lorbrena (lorlatinib) treatment resulted in increased death of neuroblastoma cells harboring ALK F1174L when co-cultured with hALK.CAR T cells compared to control CAR-T cells in culture and the combination inhibited tumor growth and increased survival in a cell line xenograft model (PMID: 38039964). 38039964
ALK R1275Q neuroblastoma sensitive hALK.CAR T cells + Lorlatinib Preclinical - Cell culture Actionable In a preclinical study, Lorbrena (lorlatinib) treatment resulted in increased death of neuroblastoma cells harboring ALK R1275Q when co-cultured with hALK.CAR T cells compared to control CAR-T cells in culture (PMID: 38039964). 38039964
ALK F1245C neuroblastoma sensitive hALK.CAR T cells + Lorlatinib Preclinical - Pdx & cell culture Actionable In a preclinical study, Lorbrena (lorlatinib) treatment resulted in increased death of cells derived from a patient-derived xenograft model of neuroblastoma harboring ALK F1245C when co-cultured with hALK.CAR T cells compared to control CAR-T cells in culture and the combination inhibited tumor growth and increased survival in a patient-derived xenograft (PDX) model (PMID: 38039964). 38039964