Cancer immunotherapy is based on functional restoration of certain signalling pathways of the host immune system that help counteract immune escape of neoplastic tissue. After being recognized as foreign, the tumour can be eliminated. In broad terms, immunotherapy encompasses a variety of diverse treatment approaches like tumour-specific monoclonal antibodies (e.g. cetuximab, bevacizumab), cancer vaccines (e.g. peptide vaccine against HPV, sipuleucel-T), adoptive cell transfer (e.g. autologous tumour-infiltrating lymphocytes, chimeric antigen receptors) and immune-modulating antibodies (e.g. immune checkpoint inhibitors) [24]. The current chapter details the last group, immune checkpoint inhibitors. These drugs, blocking the inhibitory signalling, have brought a fundamental shift in the field of precision medicine, mainly due to their potential to induce durable responses even in patients with refractory disease and cause relatively low incidence of serious adverse events. Tumour-specific antibodies are traditionally excluded from chapters on immunotherapy and are being covered elsewhere, and the remaining two categories are in early phases of clinical testing in head and neck cancer.

By means of receptor-ligand interactions, immune checkpoint pathways regulate the duration and extent of immune system activity to prevent autoimmune reactions. CTLA-4, a receptor expressed on CD4+, CD8+ and regulatory T cells, competitively disrupts the axis between tumour-specific T lymphocytes bearing CD28 receptor and stimulatory ligands CD80 (B7) and CD86 (B70) on antigen-presenting cells. Programmed death-1 (PD-1) is a receptor exposed on the surface of activated T and B lymphocytes and myeloid elements. Programmed death ligand-1 (PD-L1/CD274/B7-H1) and programmed death ligand-2 (PD-L2/CD273/B7-DC) are transmembrane proteins found on a wide variety of cells transmitting a negative signal downregulating T-lymphocyte activation. An impaired immune recognition may thus occur in case of a high fraction of CTLA-4 or PD-1 positive T cells in the tumour microenvironment or an increased expression of PD-L1 or PD-L2 by the tumour itself. Importantly, while PD-1 is a receptor for both PD-L1 and PD-L2 ligands, PD-L1 binds also to B7-1 receptor located on T cells. Consequently, although PD-1 blockage interferes with interactions between PD-1 and its two ligands, PD-L1 can still activate B7-1 receptor [23, 25].

During the application of immune checkpoint inhibitors, practitioners may encounter two specific situations concerning the distinctive kinetics of antitumour response and the characteristic, immune-related side effects. First, pseudoprogression, rare in SCCHN patients, describes a transient clinical phenomenon detectable early after treatment onset. Although resembling true neoplastic growth, it merely reflects inflammatory changes generated by immune cell infiltration. In addition, compared to classic cytotoxic agents, immunotherapy often elicits delayed responses as it may take some time to unlock the natural anticancer potential of the immune system. Consequently, this modality may not be appropriate for patients with rapidly progressive, symptomatic disease, who require prompt relief. Moreover, such a unique behaviour of cancer upon exposure to immunotherapy warrants specific immune-related response criteria, since traditional measurement guidelines do not allow for treatment beyond initial progression [26, 27]. Based on survival analysis of 592 melanoma patients treated with pembrolizumab, Hodi et al. showed that conventional Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) might underestimate the benefit of pembrolizumab in about 15 % of cases [28].

Secondly, autoimmune reactions affect a significant proportion of patients and appear usually 6–12 weeks following therapy initiation. The most frequent are endocrinopathies (hypophysitis, thyroiditis, adrenal insufficiency), diarrhoea, colitis and maculopapular rash, but they also include general symptoms like fevers, chills, and lethargy, hepatotoxic side effects, neuropathies and less commonly pneumonitis [29]. In a phase II trial exploring ipilimumab among 155 subjects with pretreated melanoma, immune-related adverse events were reported in 70 % of study population with grade 3–4 toxicities observed in 34 (22 %) patients [30]. To prevent unnecessary treatment discontinuation or enable an early re-initiation, timely diagnosis and appropriate management are warranted. Glucocorticoids can reverse nearly all immune-related adverse reactions but should be employed only for grade 3–4 or prolonged grade 2 toxicities [29].

There are several immune checkpoint inhibitors undergoing clinical evaluation in head and neck cancer. Two monoclonal antibodies of the immunoglobulin (Ig) G4 type with a high affinity for PD-1, pembrolizumab (MK-3475) and nivolumab (ONO-4538), have already been approved for treatment of advanced melanoma and lung cancer. Durvalumab (MEDI4736), atezolizumab (MPDL3280A) and avelumab (MSB0010718C) belong to an evolving category of monoclonal antibodies against PD-L1. As indicated above, ipilimumab (MDX-010) entered the market as a practice-changing drug for melanoma patients. A phase Ib study exploring ipilimumab with cetuximab and irradiation is ongoing in patients with locally advanced head and neck cancer (NCT01860430), whereas tremelimumab, another CTLA-4-directed antibody, is being studied in the recurrent/metastatic setting (see below).

SCCHN is a suitable candidate for the immunotherapeutic approach. As an immunosuppressive disease, SCCHN utilizes several mechanisms to evade immunosurveillance. It manipulates its own immunogenicity, produces immunosuppressive mediators (e.g., transforming growth factor-beta, interleukins 6 and 10) and promotes immunomodulatory cell types (myeloid-derived suppressor cells, suppressive regulatory T cells, tumour-associated macrophages) [23]. Immune dysfunction has been implicated in carcinogenesis of HPV-related oropharyngeal cancer as well as the majority of remaining SCCHN cases which are linked to smoking and alcohol. Oncogenic types of HPV, such as 16 and 18, encode E6 and E7 proteins which, together with host and environmental factors, contribute to the ability of the virus to persist in the infected organism for long periods of time. Tobacco-driven tumours harbour chronic inflammation and a high mutational load leading to increased immunogenicity. In this regard, establishment of T-cell tolerance to chronic HPV infection and overexpressed or mutated antigens poses one of the key mechanisms of immune escape [23, 31]. Recently, using gene expression-based consensus clustering, copy number profiling and HPV status, five new subtypes of SCCHN were identified to overcome some of the limitations associated with traditional classification based on anatomic site and stage. Two of these subtypes, one HPV-positive and one negative, demonstrated a prominent immune and mesenchymal phenotype with marked CD8+ lymphocyte infiltration. Such a strong activation of the immune system provides a further rationale for immunotherapy and may become a predictive biomarker for this therapeutic approach [32].

As outlined above, head and neck cancer ranks among cancers with higher somatic mutation rates. In lung cancer, a high mutation frequency was attributed to smoking and implicates increased immunogenicity due to an increment in tumour neoantigens [33]. Interestingly, the efficacy of anti-PD-1 and anti-PD-L1 antibodies seems to correlate with tobacco exposure [34–36]. This finding is intriguing within the context of head and neck cancer considering its close etiological relationship to tobacco abuse. Moreover, a subset analysis of 42 patients with melanoma, non-small-cell lung, colorectal, renal-cell and prostate cancers treated with an anti-PD-1 antibody indicated an association between PD-L1 expression on tumour cells and objective response [37]. In head and neck cancer including nasopharyngeal carcinoma, several reports confirmed that PD-L1 expression is a common event found in 46–100 % of tumour samples [38, 39]. However, these data should be used with caution because of variable quality of archival tissue specimens and differences in the used assays and scoring methods. Nonetheless, they add further evidence to the prominent immune phenotype of head and neck cancer.

The majority of R/M-SCCHN patients qualify for palliative measures with an expected survival of 6–10 months. At present, according to the pivotal EXTREME (Erbitux in first-line treatment of recurrent or metastatic head and neck cancer) trial, the platinum/5-fluorouracil/cetuximab regimen is the approved first-line systemic treatment for fit patients [40]. Unfortunately, the long-term follow-up data are far from being satisfactory underscoring the burning need for further improvement [41]. The following part of this chapter describes the preliminary results from two early clinical trials exploring pembrolizumab and durvalumab as well as the recently presented, possibly practice-changing phase III data of nivolumab.