The effects of checkpoint inhibition on head and neck squamous cell carcinoma: A systematic review
Introduction
Head and neck cancer is the sixth most frequent malignancy worldwide, with more than 650,000 reported cases annually [1] and with a continued increase in incidence [2]. The far majority of head and neck cancers are squamous cell carcinomas (HNSCC) accounting for more than 90% of the cancers located in the upper aerodigestive tract [3]. Several standard treatment modalities for HNSCC exist including surgery, chemotherapy, radiation-therapy, and epidermal growth factor receptor inhibitor (Cetuximab) [4]. Despite the development in chemotherapy, targeted radiotherapy, and surgery the estimated 5-year survival of HNSCC remains approximately 50% [5]. A potentially new therapeutic option in the treatment of HNSCC is immunotherapy targeting checkpoint inhibitors, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) or programmed cell death protein 1 (PD-1) [6]. The basic principle of immunotherapy is to activate and allow the endogenous immune system to attack the tumor cells.
PD-1 and CTLA-4 downregulate and inhibit T-cells by binding with its ligands programmed death-ligand 1 (PD-L1)/programmed death-ligand 2 (PD-L2) or CD80/CD86. Unlike the ligands of CTLA-4, which are only expressed on antigen presenting cell (APC), PD-1’s ligands are more widely expressed on leukocytes, nonlymphoid tissues, and some tumors including HNSCC [7]. Under normal conditions the immune system uses the inhibitory checkpoint pathways with CTLA-4 and PD-1 to regulate targeted activation and immune response against pathogens, while preventing the immune system from attacking itself and inducing autoimmune activity. Tumor cells take advantage of these pathways to create an immunosuppressive microenvironment in which they can hide themselves from the immune system [8]. Some tumors including HNSCC have showed an increased expression of PD-L1, the ligands for PD-1, which is thought to help create the immunosuppressive microenvironment around the tumor [9]. Blockage of the immunosuppressive effect of PD-1, PD-L1, and CTLA-4 has shown promising results as antitumor immunity, allowing T-cells to be upregulated and attack tumor cells, leading to a potentially reduction of the tumor. This has been seen in the treatment of solid tumors including HNSCC [10].
This study systematically evaluated the literature on the effects of checkpoint inhibitors on HNSCC patients. We aimed to clarify the potential benefits and harms in the use of immunotherapy targeting checkpoint inhibitors in patients with advanced HNSCC.
Section snippets
Materials and methods
This systematic review was conducted with reference to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [11].
Results
The electronic literature search generated 670 potentially eligible studies of which four studies met the inclusion criteria. Four additional study was found through reference list (Fig. 1).
Eight clinical trials (n = 1431 patients) evaluated the safety and effects of checkpoint inhibitors as a treatment for HNSCC (Table 1, Table 2). All clinical trials included patients that had been diagnosed with recurrent HNSCC and whose previous standard treatment had failed, or primary HNSCC with
Discussion
This study is the first systematic review to evaluate the effect of immunotherapy with checkpoint inhibitors for HNSCC.
We found that treating recurrent/metastatic HNSCC patients with PD-1 checkpoint inhibitors resulted in an OS ranging from 7.5 months to 14.9 months. There is a clear interval-difference of 7.4 months between the highest reported OS and the lowest. Furthermore, in patients treated with a combination of PD-L1/CTLA-4 checkpoint inhibitors resulted in an OS of 7.6 months. PD-L1 and
Conflicts of interest
The authors declare no conflicts of interest.
Funding
None.
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