TITLE:
Targeting TIGIT in NSCLC—Is There Light on the Horizon?
AUTHORS:
Susanne Reuther, Wolfram C. M. Dempke
KEYWORDS:
NSCLC, TIGIT, SKYSCRAPER Trials, KEYVIVE Studies, Domvanalimab, Ociperlimab
JOURNAL NAME:
Advances in Lung Cancer,
Vol.11 No.4,
December
6,
2022
ABSTRACT: 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.