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: Claudia Voena, Matteo Menotti, Cristina Mastini, Filomena Di Giacomo, Dario Livio Longo, Barbara Castella, Maria Elena Boggio Merlo, Chiara Ambrogio, Qi Wang, Valerio Giacomo Minero, Teresa Poggio, Cinzia Martinengo, Lucia D'Amico, Elena Panizza, Luca Mologni, Federica Cavallo, Fiorella Altruda, Mohit Butaney, Marzia Capelletti, Giorgio Inghirami, Pasi A Jänne, Roberto Chiarle
• Journal: Cancer immunology research (Cancer Immunol Res) Vol. 3 Issue 12 Pg. 1333-1343 (Dec 2015) ISSN: 2326-6074 [Electronic] United States
• PMID: 26419961 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• B7-H1 Antigen
• Cancer Vaccines
• Cd274 protein, mouse
• Pdcd1 protein, mouse
• Programmed Cell Death 1 Receptor
• Protein Kinase Inhibitors
• Pyrazoles
• Pyridines
• Crizotinib
• ALK protein, human
• Alk protein, mouse
• Anaplastic Lymphoma Kinase
• Receptor Protein-Tyrosine Kinases

Topics

• Anaplastic Lymphoma Kinase
• Animals
• B7-H1 Antigen (immunology)
• CD8-Positive T-Lymphocytes (immunology)
• Cancer Vaccines (immunology)
• Carcinoma, Non-Small-Cell Lung (genetics, therapy)
• Cell Line, Tumor
• Crizotinib
• Humans
• Lung Neoplasms (genetics, therapy)
• Mice
• Mice, Inbred BALB C
• Mice, Transgenic
• Programmed Cell Death 1 Receptor (immunology)
• Protein Kinase Inhibitors (therapeutic use)
• Pyrazoles (immunology, therapeutic use)
• Pyridines (immunology, therapeutic use)
• Receptor Protein-Tyrosine Kinases (genetics, immunology)
• Tumor Microenvironment (immunology)
• Vaccination
• Xenograft Model Antitumor Assays