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Review
. 2019 Apr 3;11(4):472.
doi: 10.3390/cancers11040472.

Targeted Therapies and Immune-Checkpoint Inhibition in Head and Neck Squamous Cell Carcinoma: Where Do We Stand Today and Where to Go?

Jens von der Grün  1 , Franz Rödel  2   3   4   5 , Christian Brandts  6   7   8 , Emmanouil Fokas  9   10   11   12 , Matthias Guckenberger  13 , Claus Rödel  14   15   16   17 , Panagiotis Balermpas  18
Affiliations
Review

Targeted Therapies and Immune-Checkpoint Inhibition in Head and Neck Squamous Cell Carcinoma: Where Do We Stand Today and Where to Go?

Jens von der Grün et al. Cancers (Basel). .

Abstract

With an increased understanding of the tumor biology of squamous cell carcinoma of the head and neck (SCCHN), targeted therapies have found their way into the clinical treatment routines against this entity. Nevertheless, to date platinum-based cytostatic agents remain the first line choice and targeting the epidermal growth factor-receptor (EGFR) with combined cetuximab and radiation therapy remains the only targeted therapy approved in the curative setting. Investigation of immune checkpoint inhibitors (ICI), such as antibodies targeting programmed cell death protein 1 (PD-1) and its ligand PD-L1, resulted in a change of paradigms in oncology and in the first approval of new drugs for treating SCCHN. Nivolumab and pembrolizumab, two anti-PD-1 antibodies, were the first agents shown to improve overall survival for patients with metastatic/recurrent tumors in recent years. Currently, several clinical trials investigate the role of ICI in different therapeutic settings. A robust set of biomarkers will be an inevitable tool for future individualized treatment approaches including radiation dose de-escalation and escalation strategies. This review aims to summarize achieved goals, the current status and future perspectives regarding targeted therapies and ICI in the management of SCCHN.

Keywords: EGFR; TKI; head and neck cancer; immune-checkpoint inhibition; mTOR; targeted therapy.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Mechanism of PD-1/PD-L1 blockade. (A): IFN-γ release upon TCR activation induces PD-L1 expression, (B): Interaction of PD-1/PD-L1 inhibits TCR signaling via SHP2, (C): Blockade of the PD-1/PD-L1 axis via atezolizumab, durvalumab, avelumab, nivolumab or pembrolizumab enhances T cell activation and proliferation; Abbreviations: IS—Intracellular space, CM—Cell membrane, ES—Extracellular space, TCR—T-cell receptor, MHC—Major histocompatibility complex I, AG—Antigen, IFN-γ—Interferon-γ, SHP2—Tyrosine phosphatase SHP-2, PD-1-Programmed cell death protein 1, PD-L1—Programmed cell death ligand 1.
Figure 2
Figure 2
Mechanism of CTLA-4 blockade. (A): Co-stimulation of TCR/CD28 induces CTLA-4 receptor expression, (B): Interaction of CTLA-4 and CD80/86 inhibits IL-2 signaling, promotes apoptosis and the secretion of immunosuppressive i cytokines, such as TGFβ, (C): CTLA-4 receptor blockade by ipilimumab or tremelimumab enhances T cell activation and proliferation; Abbreviations: IS—Intracellular space, CM—Cell membrane, ES—Extracellular space, TCR—T-cell receptor, MHC—Major histocompatibility complex I, AG—Antigen, CTLA-4—Cytotoxic T-lymphocyte antigen 4, IL-2—Interleukin-2, TGFβ—Transforming Growth Factor beta.
Figure 3
Figure 3
Mechanism of EGFR blockade. (A): Binding of EGF leads to receptor dimerization and activation of the intracellular tyrosine kinase activity and autophosphorylation, (B): Interaction of the intracellular tyrosine kinase with GRB2-SOS complex activates different pathways promoting cell growth and proliferation, (C): Extracellular EGFR receptor blockade by Cetuximab/Panitumumab and intracellular tyrosine kinase inhibitors gefitinib, afatinib, erlotinib and lapatinib impair cell growth and proliferation; Abbreviations: IS—Intracellular space, CM—Cell membrane, ES—Extracellular space, EGF—Epidermal growth factor, EGFR—Epidermal growth factor-receptor, TK—Tyrosine kinase, ATK—Activated tyrosine kinase, P—Phosphorylation, GRB2—Growth factor receptor-bound protein 2, SOS—Son of sevenless, RAS—G-protein Ras (Rat sarcoma), RAF—RAF-1 proto-oncogene serine/threonine-protein kinase, MEK—Mitogen-activated protein kinase kinase, ERK—Extracellular signal–regulated kinase, PIK3—Phosphoinositide 3-kinase, AKT—Serine/threonine-protein kinase B, mTOR—Mammalian target of Rapamycin kinase, STAT3—Signal transducer and activator of transcription 3.
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References

    1. Ferlay J., Shin H.R., Bray F., Forman D., Mathers C., Parkin D.M. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int. J. Cancer. 2010;127:2893–2917. doi: 10.1002/ijc.25516. - DOI - PubMed
    1. Sikora A.G., Toniolo P., DeLacure M.D. The changing demographics of head and neck squamous cell carcinoma in the United States. Laryngoscope. 2004;114:1915–1923. doi: 10.1097/01.mlg.0000147920.66486.bc. - DOI - PubMed
    1. Gregoire V., Lefebvre J.L., Licitra L., Felip E., EHNS-ESMO-ESTRO Guidelines Working Group Squamous cell carcinoma of the head and neck: EHNS-ESMO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 2010;21(Suppl. 5):v184–v186. doi: 10.1093/annonc/mdq185. - DOI - PubMed
    1. Bernier J., Domenge C., Ozsahin M., Matuszewska K., Lefebvre J.L., Greiner R.H., Giralt J., Maingon P., Rolland F., Bolla M., et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N. Engl. J. Med. 2004;350:1945–1952. doi: 10.1056/NEJMoa032641. - DOI - PubMed
    1. Cooper J.S., Pajak T.F., Forastiere A.A., Jacobs J., Campbell B.H., Saxman S.B., Kish J.A., Kim H.E., Cmelak A.J., Rotman M., et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N. Engl. J. Med. 2004;350:1937–1944. doi: 10.1056/NEJMoa032646. - DOI - PubMed