title: Efficacy of a Cancer Vaccine against ALK-Rearranged Lung Tumors.
abstract: Non-small cell lung cancer (NSCLC) harboring chromosomal rearrangements of the anaplastic lymphoma kinase (ALK) gene is treated with ALK tyrosine kinase inhibitors (TKI), but the treatment is successful for only a limited amount of time; most patients experience a relapse due to the development of drug resistance. Here, we show that a vaccine against ALK induced a strong and specific immune response that both prophylactically and therapeutically impaired the growth of ALK-positive lung tumors in mouse models. The ALK vaccine was efficacious also in combination with ALK TKI treatment and significantly delayed tumor relapses after TKI suspension. We found that lung tumors containing ALK rearrangements induced an immunosuppressive microenvironment, regulating the expression of PD-L1 on the surface of lung tumor cells. High PD-L1 expression reduced ALK vaccine efficacy, which could be restored by administration of anti-PD-1 immunotherapy. Thus, combinations of ALK vaccine with TKIs and immune checkpoint blockade therapies might represent a powerful strategy for the treatment of ALK-driven NSCLC.
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.|Center for Experimental Research and Medical Studies (CERMS), Città della Salute e della Scienza, Torino, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Voena
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.|Center for Experimental Research and Medical Studies (CERMS), Città della Salute e della Scienza, Torino, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Menotti
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.|Center for Experimental Research and Medical Studies (CERMS), Città della Salute e della Scienza, Torino, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Mastini
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.|Center for Experimental Research and Medical Studies (CERMS), Città della Salute e della Scienza, Torino, Italy.
authors.forename: Filomena
authors.initials: F
authors.lastname: Di Giacomo
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.|Molecular Imaging Center, University of Torino, Torino, Italy.
authors.forename: Dario Livio
authors.initials: DL
authors.lastname: Longo
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.|Center for Experimental Research and Medical Studies (CERMS), Città della Salute e della Scienza, Torino, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Castella
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.|Center for Experimental Research and Medical Studies (CERMS), Città della Salute e della Scienza, Torino, Italy.
authors.forename: Maria Elena Boggio
authors.initials: MEB
authors.lastname: Merlo
authors.affiliation: Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain.
authors.forename: Chiara
authors.initials: C
authors.lastname: Ambrogio
authors.affiliation: Department of Pathology, Children's Hospital Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.|Center for Experimental Research and Medical Studies (CERMS), Città della Salute e della Scienza, Torino, Italy.
authors.forename: Valerio Giacomo
authors.initials: VG
authors.lastname: Minero
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.|Center for Experimental Research and Medical Studies (CERMS), Città della Salute e della Scienza, Torino, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Poggio
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.|Center for Experimental Research and Medical Studies (CERMS), Città della Salute e della Scienza, Torino, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Martinengo
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.|Center for Experimental Research and Medical Studies (CERMS), Città della Salute e della Scienza, Torino, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: D'Amico
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.|Center for Experimental Research and Medical Studies (CERMS), Città della Salute e della Scienza, Torino, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Panizza
authors.affiliation: Department of Health Sciences, University of Milano-Bicocca, Milano, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Mologni
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.|Molecular Biotechnology Center, University of Torino, Torino, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Cavallo
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.|Molecular Biotechnology Center, University of Torino, Torino, Italy.
authors.forename: Fiorella
authors.initials: F
authors.lastname: Altruda
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.|Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Mohit
authors.initials: M
authors.lastname: Butaney
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.|Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Marzia
authors.initials: M
authors.lastname: Capelletti
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.|Center for Experimental Research and Medical Studies (CERMS), Città della Salute e della Scienza, Torino, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Inghirami
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.|Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.|Belfer Institute for Applied Cancer Science, Dana Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Jänne
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.|Center for Experimental Research and Medical Studies (CERMS), Città della Salute e della Scienza, Torino, Italy.|Department of Pathology, Children's Hospital Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Roberto
authors.initials: R
authors.lastname: Chiarle
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D060890:B7-H1 Antigen / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000628:therapy*; D045744:Cell Line, Tumor; D000077547:Crizotinib; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011720:Pyrazoles / Q000276:immunology / Q000627:therapeutic use; D011725:Pyridines / Q000276:immunology / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000276:immunology*; D059016:Tumor Microenvironment / Q000276:immunology; D014611:Vaccination; D023041:Xenograft Model Antitumor Assays
chemical_list: D060890:B7-H1 Antigen; D019496:Cancer Vaccines; C498919:Cd274 protein, mouse; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases