Reference Detail

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

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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
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Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role
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Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
hALK.CAR T cells	hALK.CAR T cells	4	1

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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).

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Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
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Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
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
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 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 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 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 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 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 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

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