The anaplastic lymphoma kinase (ALK) receptor is an oncogenic driver specifically expressed by neuroblastoma. Bergaggio, Tai, et al. developed CAR-T recognizing the ALK extracellular domain. In mouse models for ALK-driven neuroblastoma, ALK.CAR-T limited tumor growth and prolonged survival, without toxicity. A humanized version of ALK.CAR-T had cytolytic activity against metastasized neuroblastoma, but was limited if ALK expression was low. Treatment with ALK inhibitors increased ALK expression, and the combination of ALK inhibitors and ALK.CAR-T further reduced tumor growth and improved survival in mice bearing ALK-low tumors.
Contributed by Maartje Wouters
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.
Author Info: (1) Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA. (2) Department of Pathology, Boston Children's Hospital and Harvard Medic
Author Info: (1) Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA. (2) Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA. (3) Department of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy. (4) Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA. (5) Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. (6) Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA. (7) Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA; Department of Radiation Oncology, Weill Cornell Medicine, New York, NY 10065, USA. (8) Department of Oncology, University of Torino, 10126 Torino, Italy. (9) Department of Medical Science, University of Torino, 10126 Torino, Italy. (10) Koch Institute and MIT, Cambridge, MA 02139, USA. (11) Celldex Therapeutics, New Haven, CT 06511, USA. (12) Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy. (13) Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy. (14) Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA. (15) Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA. (16) Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA. (17) Koch Institute and MIT, Cambridge, MA 02139, USA. (18) Department of Oncology, University of Torino, 10126 Torino, Italy. (19) Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. (20) Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. (21) Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA; Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy. Electronic address: roberto.chiarle@childrens.harvard.edu.
