16 Chapter 1 The advent of immunotherapy in the neoadjuvant setting of locally advanced disease Unfortunately, 5-year overall survival after surgery stagnates at 50% (16, 17). Additionally, a substantial part of HNSCC patients that are treated with surgery suffer from problems associated with swallowing, speech, or aesthetics (64). These poor outcomes and high morbidities require new treatment options that not only improve survival, but also de-intensify the current treatment protocols (58). The combination of immune checkpoint inhibitors targeting PD-1 and CTLA-4 , another immune checkpoint protein, specifically nivolumab and ipilimumab, has been proven more effective than either monotherapy in advanced melanomas (65). Although the additive value of adding anti-CTLA-4 (tremelimumab) to anti-PD-L1 (durvalumab), the activating ligand of PD-1, was not observed for recurrent and metastatic HNSCCs (66, 67), there is limited evidence that anti-PD-1 monotherapy has modest effects in the curative neoadjuvant setting of human papilloma virus (HPV)-negative HNSCCs with major pathological tumor responses (pTR), defined as pTR in > 90% observed for the primary tumor, ranging from 7 to 14% (68, 69). Schoenfeld et al. (68) also showed that combining nivolumab and ipilimumab in the neo-adjuvant setting was more effective compared to nivolumab monotherapy. The latter was confirmed by Vos et al. in the IMCISION trial which showed a major pathological response (MPR) rate of 35% for patients treated in the nivolumab and ipilimumab arm, and 17% for those in the nivolumab arm (58). Knowing that none of the MPR patients developed recurrent disease within 24 months, indicates that neoadjuvant immunotherapy is a promising treatment protocol for HNSCC patients that are treated with surgery (58). Notwithstanding the developments in the treatment of OSCC, there is an interest to implement targeted therapies and immune checkpoint inhibitors – other than cetuximab, pembrolizumab, and nivolumab. Among the long list of potentially interesting molecular targets for therapy is the receptor tyrosine kinase (RTK) MET (hepatocyte growth factor receptor) (10, 70, 71). The receptor tyrosine kinase MET, a potential target for therapy in HNSCC? MET and its physiological ligand hepatocyte growth factor/scatter factor (HGF/SF) were discovered in the mid-1980s (72). MET is predominanty expressed on the surface of epithelial cells, HGF/SF is expressed by cells of mesenchymal origin – e.g. fibroblast – residing in the surrounding stroma (73). Signaling via this ligand-receptor
RkJQdWJsaXNoZXIy MTk4NDMw