Targeting TIGIT in NSCLC—Is There Light on the Horizon?

Non-small cell lung cancers (NSCLCs) represent over 80% of all malignant lung tumours and are one of the leading causes of cancer death throughout the world. First- and second-line treatment of advanced or metastatic NSCLCs has changed dramatically during the last two decades with the development of novel immunotherapies (e.g., checkpoint inhibitors targeting PD-1, PD-L1, and CTLA-4) sparing NSCLC patients from the toxic effects of chemotherapy. However, only 15% - 20% of all patients respond to treatment. In order to improve response rates, experimental and clinical evidence has provided the basis for further evaluating the combination of co-stimulatory and inhibitory monoclonal antibodies to improve the anti-tumour immune response. Innovative second- and third-generation immuno-oncology drugs are currently evaluated in ongoing phase I-III trials (either alone or in combination) including the new checkpoint inhibitor target TIGIT (T cell immunoreceptor with Ig and ITIM domains). TIGIT functions as an inhibitory immunoglobin receptor which is overexpressed by different immune cells including effector and memory CD4+ T and CD8+ T cells, regulatory T cells (Tregs), follicular T helper cells (Tfh), and natural killer cells. Targeting the interaction between the receptors of the TIGIT receptors (e.g., CD96, CD112R, CD226, TIGIT and their corresponding binding partners) has become an innovative strategy for the next concepts of cancer immunotherapy that has the potential to synergize with PD-1/PD-L1checkpoint inhibition. Currently, four anti-TIGIT monoclonal antibodies are currently being studied in phase III trials in NSCLCs: 1) tiragolumab (SKYSCRAPER programme); 2) vibostolimab (KEYVIVE programme); 3) domvanalimab (ARC programme), and 4) ociperlimab (AdvanTIG programme). The vast majority of these studies are ongoing; however, the SKYSCRAPER-01 trial (tiragolumab in NSCLC) and the SKYSCRAPER-02 trial (tiragolumab in SCLC) were negative and did not meet their primary endpoint. The underlying preclinical and clinical mechanisms of these unexpectedly negative studies are currently far from being clear and the results from currently recruiting clinical studies are eagerly awaited to shed some additional light on these results. From 2021 onwards different TIGIT family receptors are currently evaluated in over 25 clinical trials (phase I-III), however, a lot of preclinical and clinical research is ongoing at different research sites which will help to identify novel immune checkpoint targets with improved activity against malignancies across all histologies.