ALK Inhibitors Increase ALK Expression and Sensitize Neuroblastoma Cells to ALK.CAR-T Cells

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2023 Dec 1

PMID 38039964

Authors

Elisa Bergaggio

Wei-Tien Tai

Andrea Aroldi

Carmen Mecca

Elisa Landoni

Manuel Nuesch

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

Affiliations

Soon will be listed here.

Abstract

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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