Elsevier

Cancer Treatment Reviews

Volume 65, April 2018, Pages 78-86
Cancer Treatment Reviews

Anti-Tumour Treatment
Immuno-oncology in head and neck squamous cell cancers: News from clinical trials, emerging predictive factors and unmet needs

https://doi.org/10.1016/j.ctrv.2018.03.003Get rights and content

Highlights

Abstract

According to the new determinants of cancer immunity, head and neck squamous cell cancer (HNSCC) has to be considered as an immunogenic tumor for the relatively high number of somatic mutations giving rise to neoantigens recognized by T cell. HNSCC develop at a significant rate despite the antitumoral immune response indicating the existence of effective escape mechanisms. The lack of antigen presentation or co-stimulatory molecules required and immunosuppressive phenomena established by the tumor or the host microenvironment impair immune-mediated recognition and cancer control. Echoing the success in melanoma and NSCLC, strategies aimed to reverse this process and enhance the antitumor immunity are rapidly developing in HNSCC, as monotherapies, multidrug immunotherapies or associations with well-recognized treatments, like radiation and systemic therapies.

According to the first published data, immunotherapy has shown promising results in the management of recurrent and metastatic (r/m) HNSCC. Anti-PD-1 blockers have been recently approved by US and EU regulatory agencies in this setting. The encouraging results in r/m HNSCC prompted the incorporation of this approach also in the treatment of locally advanced disease. However, the strategies for the rational and evidence-based combinations to maximize clinical benefit are only starting to emerge. In this view, knowing in depth the specific properties of HNSCC and the underlying immunological conditions of the bearing hosts is an essential step. The role of immune system in the development and the management of HNSCC, the main mechanisms of tumor escape and the most recent results from clinical trials will be discussed herein.

Section snippets

Rationale for exploring immunotherapy in HN cancer

Head and neck cancers consist in a heterogeneous group of tumors with different natural history, that strictly depends on histology, anatomical site of origin and tumor biology. Well-known risk factors are alcohol abuse, tobacco smoking [1], and human papillomavirus (HPV) infection [2].

Head and neck squamous cell carcinoma (HNSCC), as many other cancers, develops in the context of immune suppression [3]. Indeed, a deregulated immune system in terms of cancer immunosurveillance is a key point in

What we learned from clinical trials till now

All the preclinical observations about the immunogenicity of HNSCC represent a strong rational to the use of immunomodulating strategies for overcoming immune deregulation in these patients. Involved inblocking the activity of chronically stimulated T cells and causing their functional exhaustion., immune checkpoint such as CTLA4 and PD-1 are over-expressed in HNSCC microenvironment [22]. Antibodies directed against PD-1/PD-L1 and CTLA4have been assessed also in the treatment of metastatic

Combination therapeutic strategies

Anti-tumor activity of immune checkpoint inhibitors used as monotherapy, in terms of both survival and response rate, is promising, but we are still far from achieving a satisfactory goal in managing platinum resistant HNSCC patients, whose prognosis remain dismal in the great majority of cases. The use of multiple immunotherapeutic agents, aimed at promoting more efficient immune responses and possibly overcoming additional escape mechanism, are being developed in RM setting.

Immunotherapy and radiotherapy

In locally advanced setting multiple therapeutic combinations of immunotherapy are also under investigation. Specifically, radiation therapy may increase the capability of the immune system to exert its function through an increase in tumor neoantigens, due to the mutagenic activity of radiation [53], boost in antigen presentation [54], enhanced killing by CD8+ T-cells [55] and improved cytokines production triggering a acute pro-inflammatory cascade [56]. DNA damage itself is a potent

Predictive factors of response

To date, no definite predictive factors of response have been identified for immunotherapy in HNSCC. Tumor tissue PD-L1 expression is associated with an immune-active microenvironment, thus theoretically it could be the strongest predictive factor of response to PD-1/PD-L1 inhibitors [68]. In line with the strong immunogenicity of this cancer, tumor tissue PD-L1 expression was observed in 45–80% of HNSCC [69].

Additional druggable pathways of tumor immune escape

As already mentioned, many are the mechanisms described to impair immune recognition in HNSCC [16]. In addition, a sort of specific phenotype that characterized HNSCC and possibly create a particularly immune suppressive microenvironment is related to the enrichment in cancer stem-like cells [84] which have been shown, together with signatures associated to epithelial to mesenchymal transition and hypoxia, to identify tumors resistant to immune checkpoint inhibitors. [85] The recruitment at

The unmet needs

In head and neck immuno-oncology, many are the unmet clinical needs. Among them is the identification of robust predictive factors to better select patients potentially benefitting from immune checkpoint inhibitors, so avoiding toxicities and applying alternative strategies to non-responding subjects.

In this regard, the choice should fall not only on molecular or circulating biomarkers, but also on clinical characteristics able to discover the responding patients.

The identification of a

Conclusions

The first encouraging results with checkpoint inhibitors involved recurrent or metastatic platinum-resistant disease.

The actual mainstays of the management of head and neck cancer in the curative setting are surgery and/or radiotherapy with or without chemotherapy. To date, no definitive data about the role of immune checkpoint blockade in HNSCC locally advanced disease are available. However, the promising data in adjuvant setting achieved in melanoma and the promising results in stage III

Conflicts of interest

Lisa Licitra reports grants and personal fees from Eisai, MSD, Boehringer Ingelheim, Novartis, Astrazeneca, Roche; personal fees from BMS; grants, personal fees and other (travel expenses) from Merck-Serono, Bayer, Debiopharm, Sobi.

Laura Locati reports honoraria from Eisai.

Paolo Bossi reports honoraria or consultation fees from Roche, Merck Serono, Mundipharma, Kyowa Kyrin, Astra Zeneca.

All remaining authors have declared no conflicts of interest.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

References (102)

  • D.P. Zandberg et al.

    The role of the PD-L1:PD-1 pathway in squamous cell carcinoma of the head and neck

    Oral Oncol

    (2014)
  • S. Turajlic

    Insertion-and-deletion-derived tumour-specific neoantigens and the immunogenic phenotype: a pan-cancer analysis

    Lancet Oncol

    (2017)
  • X. Qian

    Biology and immunology of cancer stem(-like) cells in head and neck cancer

    Crit Rev Oncol Hematol

    (2015)
  • W. Hugo

    Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma

    Cell

    (2016)
  • V. Kumar

    The nature of myeloid-derived suppressor cells in the tumor microenvironment

    Trends Immunol

    (2016)
  • K. Utispan et al.

    Fibroblasts and macrophages: Key players in the head and neck cancer microenvironment

    J Oral Biosci

    (2017)
  • M.R. Cassidy

    Neutrophil to lymphocyte ratio is associated with outcome during ipilimumab treatment

    EBioMed

    (2017)
  • E. Saada-Bouzid

    Hyperprogression during anti-PD-1/PD-L1 therapy in patients with recurrent and/or metastatic head and neck squamous cell carcinoma

    Ann Oncol

    (2017)
  • M. Hashibe

    Interaction between tobacco and alcohol use and the risk of head and neck cancer: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium

    Cancer Epidemiol Biomarkers Prev

    (2009)
  • M.L. Gillison

    Distinct risk factor profiles for human papillomavirus type 16-positive and human papillomavirus type 16-negative head and neck cancers

    J Natl Cancer Inst

    (2008)
  • A. Duray

    Immune suppression in head and neck cancers: a review

    Clin Dev Immunol

    (2010)
  • F.M. Burnet

    Immunological recognition of self

    Science

    (1961)
  • A.N. Houghton et al.

    Immune recognition of self in immunity against cancer

    J Clin Invest

    (2004)
  • T.N. Schumacher et al.

    Neoantigens in cancer immunotherapy

    Science

    (2015)
  • F.M. Burnet

    The concept of immunological surveillance

    Prog Exp Tumor Res

    (1970)
  • R.D. Schreiber et al.

    Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion

    Science

    (2011)
  • R. Kim et al.

    Cancer immunoediting from immune surveillance to immune escape

    Immunology

    (2007)
  • S. Stevanovic

    Landscape of immunogenic tumor antigens in successful immunotherapy of virally induced epithelial cancer

    Science

    (2017)
  • Mandal R, et al. The head and neck cancer immune landscape and its immunotherapeutic implications. JCI Insight...
  • T.A. Barnes et al.

    HYPE or HOPE: the prognostic value of infiltrating immune cells in cancer

    Br J Cancer

    (2017)
  • H. Takahashi

    Immunosuppressive activity of cancer-associated fibroblasts in head and neck squamous cell carcinoma

    Cancer Immunol Immunother

    (2015)
  • M. Meissner

    Defects in the human leukocyte antigen class I antigen processing machinery in head and neck squamous cell carcinoma: association with clinical outcome

    Clin Cancer Res

    (2005)
  • S. Ludwig

    Suppression of lymphocyte functions by plasma exosomes correlates with disease activity in patients with head and neck cancer

    Clin Cancer Res

    (2017)
  • X. Qi

    Advances in T-cell checkpoint immunotherapy for head and neck squamous cell carcinoma

    Onco Targets Ther

    (2017)
  • C.C. Tong et al.

    Recognizing and reversing the immunosuppressive tumor microenvironment of head and neck cancer

    Immunol Res

    (2012)
  • B. Solomon et al.

    Head and neck squamous cell carcinoma: Genomics and emerging biomarkers for immunomodulatory cancer treatments

    Semin Cancer Biol

    (2018)
  • S. Lyford-Pike

    Evidence for a role of the PD-1:PD-L1 pathway in immune resistance of HPV-associated head and neck squamous cell carcinoma

    Cancer Res

    (2013)
  • R.L. Ferris

    Nivolumab for recurrent squamous-cell carcinoma of the head and neck

    N Engl J Med

    (2016)
  • S.L. Topalian

    Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab

    J Clin Oncol

    (2014)
  • R.B.J.G. Haddad et al.

    1043O - treatment beyond progression with nivolumab in patients with recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) in the phase 3 Checkmate 141 study: a biomarker analysis and updated clinical outcomes

    Ann Oncol

    (2017)
  • Ferris RL, et al. Nivolumab (Nivo) vs investigator’s choice (IC) in patients with recurrent or metastatic (R/M)...
  • H.S. Kim

    Association between PD-L1 and HPV status and the prognostic value of PD-L1 in oropharyngeal squamous cell carcinoma

    Cancer Res Treat

    (2016)
  • P. Balermpas

    The PD-1/PD-L1 axis and human papilloma virus in patients with head and neck cancer after adjuvant chemoradiotherapy: A multicentre study of the German Cancer Consortium Radiation Oncology Group (DKTK-ROG)

    Int J Cancer

    (2017)
  • J. Bauml

    Pembrolizumab for Platinum- and Cetuximab-Refractory Head and Neck Cancer: Results From a Single-Arm. Phase II Study

    J Clin Oncol

    (2017)
  • E.E.H. Cohen et al.

    LBA45_PR Pembrolizumab (pembro) vs standard of care (SOC) for recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC): Phase 3 KEYNOTE-040 trial

    Ann Oncol

    (2017)
  • Segal NH, Ou SHI, Balmanoukian AS, Massarelli E, Brahmer JR, Weiss J, et al. 949O - Updated safety and efficacy of...
  • Segal, NH, Ou, SH, Balmanoukian, AS, Massarelli, E, Brahmer, JR, Weiss, J, et al. 949O - Updated safety and efficacy of...
  • D.A. Zandberg et al.

    1042O - Durvalumab for recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC): preliminary results from a single-arm, phase 2 study

    Ann Oncol

    (2017)
  • R.B. Bahleda et al.

    1044O - Long-term safety and clinical outcomes of atezolizumab in head and neck cancer: phase ia trial results

    Ann Oncol

    (2017)
  • Wei, SC, et al. Distinct Cellular Mechanisms Underlie Anti-CTLA-4 and Anti-PD-1 Checkpoint Blockade. Cell 2017;170(6):...
  • Cited by (0)

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