Crizotinib – a tyrosine kinase inhibitor that stimulates immunogenic cell death

• Main Authors: Peng Liu, Liwei Zhao, Oliver Kepp, Guido Kroemer
• Format: Article
• Language: English
• Published: Taylor & Francis Group 2019-07-01
• Series: OncoImmunology
• Subjects: immune checkpoint blockade; immunotherapy; non-small cell lung cancer; pd-1
• Online Access: http://dx.doi.org/10.1080/2162402X.2019.1596652

Crizotinib is a tyrosine kinase inhibitor (TKI) approved for the treatment of non-small cell lung cancers (NSLCL) and lymphomas expressing activating translocations or mutations of oncogenic tyrosine kinases (in particular ALK and ROS1). We recently observed that high-dose (final concentration in vivo: ~10 µM) crizotinib can induce immunogenic cell death (ICD) in cancer cells lacking ALK/ROS1 activation through off-target effects that require the inhibition of several other tyrosine kinases. When combined with cisplatin (which alone does not induce ICD), crizotinib sensitizes NSCLC models to subsequent immunotherapy with PD-1 blockade, allowing to cure more than 90% of established orthotopic cancers. Of note, simultaneous treatment of mice with cisplatin, crizotinib and PD-1 blocking antibodies causes acute hepatotoxicity that can be avoided by a sequential regimen involving initial treatment with cisplatin plus crizotinib, followed by PD-1 blockade one week later. It will be important to translate these results obtained in mice into a clinical trial in NSCLC patients.