In the last 40 years, treatment of head and neck squamous cell cancer (HNSCC) did not change dramatically. Radiotherapy and platinum-based chemotherapy represent the backbone treatments for locally advanced HNSCC (LA-HNSCC) and are offered for resected high-risk LA-HNSCC [1-5]. In 2006, the trial by Bonner et al. [6] introduced a second standard treatment: bio-radiation. Relapsed metastatic head and neck cancer (RM-HNC) evolved even slower than LA-HNC.

Platinum combination was the standard treatment until the extreme study reported the benefit of Cetuximab combination [7]. Since then, the extreme regimen represents the new first-line standard of care for RM-HNC. An established second-line treatment has never existed in RM-HNC, up to the approval of immune checkpoint inhibitors (ICIs) [8]. Therefore, the 5-year prognosis remains around 50% at 5 years and median overall survival (OS) in RM-HNC is less than 11 months [7].

However, immune-modulating treatments appear to have a clear clinical benefit for RM-HNSCC and this benefit seems to be independent of previous treatment, even being observed among patients who have received multiple lines of therapy and who have been assumed to have exhausted all options. Two drugs targeting the PD-1/PD-L1 axis, Nivolumab and pembrolizumab, have achieved the approval for second-line treatment of RM-HNC (study KEYNOTE-012 [9] and CheckMate 141 [10]) [11]. Moreover, Durvalumab, an anti-PD-L1 drug, also showed a benefit in terms of disease control rate in pretreated HNSCC patients [12].

It is reasonable to think that these ICIs will move soon to first-line and will be introduced as companion drugs in the multi-agent treatment of LA-HNC. In the meanwhile, new immunotherapies are in clinical development and some of them have already reached the phase III [11]. However, although the results (slightly higher but longer responses) justify the enthusiasm, they are some warning on immune-resistance. Indeed, a high proportion of patients is resistant or acquires resistance to these therapeutic strategies. The latter findings may reflect, at least in some cases, the inability of the immunotherapeutic strategies used to eradicate (Table 1 summarizes published results with ICI in HNSCC; Table 2 reports a confront with standard methotrexate as published in LUX1 study) [9,10,13-15]. This paper addresses the new data on the therapy of HNSCC and discusses the biological basis of immunotherapy in this disease.

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According to Blank et al. [16], the mutational load (ML) of HNC is in between liver cancer and kidney cancer, tumors known for their high immunogenicity. This is related to the large number of mutations induced by smoking, the upmost risk factor for these tumors. However, the head and neck regions host two different virus-induced tumors: oropharynx cancer, related to human papillomavirus (HPV), and undifferentiated nasopharynx cancer, related to Epstein-Barr Virus (EBV).

Looking at environmental induced tumors, it is expected that they are able to generate robust immune response, as supported by the high immune cells infiltration, due to their high ML [17]. Virus-induced HNC are different from the environmental-induced HNC. For example, both the virus-induced tumors show a much lower ML rather than those related to smoking abuse [18,19]. According to Seiwert et al. [19], there is a direct relationship between ML and benefit from immunotherapy.

However, clinical available data do not show any clear difference of the outcome between “environmental” and “virus-related” HNC. Generically, we might speculate that the virus immunogenicity could compensate for the lower mutational burden of virus induced HNC. Indeed, invading DNA viruses or transfected DNA, activate stimulator of interferon genes (STING), a signaling molecule located in the endoplasmic reticulum, leading to the transcription of many immune genes. This in turn promotes an immune response against pathogens and cancer cells starting an interferon (IFN) type I over expression which is toll-like receptor (TLR) independent [20]. In addition, STING, different from the TLRs, is widely expressed in various cell types, including endothelial, epithelial and haemopoietic, such as T cells, dendritic cells dendritic cells (DCs), and in particular, plasmacytoid DCs [21].

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Combining anti-PD-1 and anti-CTLA-4 agents has been approved for melanoma, and it looks promising in lung cancer and renal cancer [22]. Several studies are ongoing both in first- and second-line combining anti-PD-1 and anti-CTLA-4. Immuno-monotherapy regimens for HNSCC have yielded modest results, with few good responders (long-lasting and tumor response) [11]. It may be hypothesized that monotherapy is not able to overcome the numerous mechanism of immune escape. Combinatorial immunotherapy should increase response based on biological rationale of acting at a different ligand and function. It has been reported that HNSCCs have a high infiltration of Tregs, so although inflamed tumor immune phenotype, response might be unsatisfactory. Moreover, in immune excluded tumor, microenvironment is rich of immunosuppressive factors that avoid immune response (high interstitial pressure due to vascular endothelial growth factor [VEGF], metabolic alteration due to indoleamine 2, 3-dioxygenase [IDO], natural killer impairment related to several other immune regulators such as KIR, CD137, TIM3, LAG3) [23].

A promising approach is to combine IDO1 inhibitor with ICI: IDO1 over expression has been associated with poor survival in HNSCC. The role of this enzyme is very important, it transforms tryptophan in kynurenine, on the one hand, tryptophan deprivation affect cytotoxic lymphocytes, on the other hand, excess of kynurenine induce their apoptosis. Preliminary results of the combination epacadostat (a potent, selective oral IDO1 inhibitor) plus pembrolizumab reported encouraging response rates (34% and 14% in second and third lines and more heavily pretreated patients) [24]; epacadostat also demonstrated promising activity in combination with other checkpoint inhibitors in other solid tumors, including melanoma, urothelial carcinoma, renal cell carcinoma, and non-small cell lung cancer. Recent advances demonstrated the role of STING, TLR and retinoic induced gene receptors like to induce effective response. However, although TLRs are key mediators of immune responses, TLR agonists in combination with bio and chemotherapy failed to improve progression-free survival (PFS). In the Active 8 study, no advantage was reported with or without motolimod therapy, a selective small-molecule agonist of TLR8. It must be remembered that not all TLRs are the cytosolic and this might explain differences in efficacy [25]. Nevertheless, the combination of motolimod with Cetuximab in patients with HNSCC showed a disease control rate of 54% [26]. A phase IB is ongoing in the neoadjuvant setting.

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Based on biologic knowledge, immunotherapy has been associated respectively with radiotherapy or chemotherapy in order to induce cancer death and a self-vaccination; with vaccination to target viral antigens and with biotherapy to target proliferation pathways that crosstalk with immune system. The rationale is to elicit a strong immune response activating microenvironment while administering immunotherapy [27]. Preclinical evidence showed that radiotherapy upregulates PD-L1 within 24 to 48 hours; in animal models increase in survival has been reported [28].

A second partner with a strong biological rationale is anti-epidermal growth factor receptor (EGFR) Cetuximab (Erbitux) (https://clinicaltrials.gov). Several demonstrations evidenced that at least a part of Cetuximab effect depends on antibody-mediated cytotoxicity, this activity involves principally natural killer cells. Eight studies are ongoing combining ICI+Cetuximab±respectively with Nivolumab (two studies), Pembrolizumab (two studies), Durvalumab (three studies) and Avelumab (two studies) [29-32].

There are also at least three phase III trials for LA-HNC. Early reports confirmed that pembrolizumab in combination with weekly cisplatin-based chemoradiotherapy (CRT) is safe and does not significantly impair radiation or chemotherapy dosing (ClinicalTrials.gov Identifier: NCT02586207) [33]. The goal of this combination (ICI+CRT) is to increase distant metastases free survival and OS in stage III–IV HNC. These studies will inform on the correct algorithm: providing evidence if sequential versus concomitant ICI has to be preferred.

In the neoadjuvant setting, extraordinary results point out the time of ICI therapy: earlier than recurrent/metastatic (R/M) disease? Benefit after one dose of pembrolizumab before surgery was obtained in 48% of patients (95% confidence interval, 26% to 70%; ClinicalTrials.gov Identifier: NCT02296684) while after two doses of Nivolumab 11 of 23 patients reported RECIST (Response Evaluation Criteria in Solid Tumors) disease reduction [34]. Moreover, targeting HPV and EBV in association with ICI has showed enthusiastic preclinical results [35,36]. Several trials are ongoing combining definitive chemotherapy or CRT and HPV/EBV vaccines and ICI. Tables 3 and 4 summarize ongoing phase III trials in LA-HNC and RM-HNC.

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Clinical trials (CheckMate 141, KEYNOTE-012, 055, 040) published (and presented) so far focus on second-line treatment. Lessons learned from these trials allow drawing some initial information on toxicity and activity [9,10-14,37].

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PD-1/PD-L1-targeted drugs have obvious advantages over traditional therapeutic regimens in terms of overall response rate, survival, and safety but their efficacy is still disappointing. As single agents, these therapies have response rated in the range of 14%–32% [11]. Several mechanisms can elicit the resistance of HNC cells to immunotherapy: (1) immunosuppressive factors in microenvironment: abundance of FoxP3+ and deregulation of CCL22-CCR4 axis has been reported [42]; constitutive activation of STAT3 and expression of VEGF, interleukin (IL)-6, IL-10. HNC inhibits chemokines in a transforming growth factor beta and VEGF dependent manner [43]. (2) Impaired human leukocyte antigen (HLA)-mediated cancer cell recognition: HNC over-express EGFR. Over-expression and over-activation of EGFR not only induces oncogenic transformations but also downregulates the expression of antigen presenting machinery. EGFR activates a protein phosphatase (SHP2) which dephophorilated STAT1 (signal transducer and activator of transcription 1) leading to reduced HLA class I dependent antigen presentation [44]. (3) PD-1/PD-L1 expression: a downregulation is mediated in a JAK2/STAT1 dependent manner. Moreover, EGFR blockade downregulated IFN-γ-dependent PD-L1 expression according to Concha-Benavente and Ferris [44]. Interestingly, EGFR also promotes stabilization of PD-L1 surface expression through glycosylation of its extracellular domain [45]. (4) Several immune modulators were reported to negatively affect T cells activity. For example, VISTA (V-domain Ig suppressor of T cell activation), a recently discovered protein involved in the checkpoint inhibitors, is overexpressed in HNSCC [23].

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ML and gene expression profile (GEP) were utilized in some American institution to assess in order to identify responders. ML and GEP are independently predictive of response to pembrolizumab in HPV–/EBV– patients with HNSCC; GEP was predictive regardless of viral status [11]. ML and GEP may have utility in characterizing responses to anti PD-1 therapies and novel cancer regimens in HNSCC. Mattox et al. [46] demonstrated, by analyzing archival tissue stained for PD-L1, that PD-L1 status in RM-HNC patients did not directly correlated, as in other solid tumors, with OS nor PFS NCT02543476.

In the randomized CheckMate 141 trial, PD-L1 expression was assessed on tumor cells of 72% of the patients. Patients were divided in two prespecified subgroups (expression ≥1% and <1%). The magnitude of survival benefit was greater in PD-L1 ≥1% population, hazard ratio for death 0.55 (0.36 to 0.86) vs. 0.89 (0.54 to 1.85), whereas no advantage was demonstrated for increasing PD-L1 expression [10]. The expanded cohort of the KEYNOTE-012 trial used two different methods to define PD-L1 positivity: the combined positive score (CPS) defined as ≥1% of expression in both tumor and mononuclear inflammatory cells, and the tumor proportion score defined as ≥1% of expression only in tumor cells [9]. The study identified a relation between PD-L1 positivity and relative ratio (RR) only with the combined positivity score (22% vs. 4%, P=0.021). Similarly, statistically significant differences for PFS and OS were observed for PD-L1 positive patients using CPS [13].

On the contrary, in the KEYNOTE-055 study, using the same CPS score, PD-L1 positivity was not demonstrated to be predictive of response, the response rate being 12% even in PD-L1 negative patients, compared to 18% in positive patients. Interestingly, RR was higher in patients with ≥50% [37]. In the KEYNOTE-040, Cohen et al. [14] presented the results among the difference in PD-L1 CPS score ≥1% versus the tumoral positive score ≥50%, these results confirm the role of this marker, but no comparison can be obtained among tumoral positive score and CPS as they used two different levels [14]. Therefore, PD-L1 is a marker but we cannot assume it is the marker; several factors contribute to the immune continuum and a better knowledge is required to have a reproducible and safe predictive marker. Muller et al. [47] reported a strong correlation between expression of PD-L1 and reduced OS time.

Other biomarkers appear fascinating such as PD-L1 evaluation in circulating cell (blood biopsy), characterization of tumor infiltrating cells and PD-L2. This latter was studied by Yearley et al. [48] on 180 HNSCC patients. They showed that response was greater in patients positive for both PD-L1 and PD-L2 (27.5%) than those positive only for PD-L1 (11.4%). PD-L2 status was also a significant predictor of PFS with pembrolizumab independent of PD-L1 status. Longer median times for PFS and OS were observed for PD-L2-positive than PD-L2-negative patients.

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Immunotherapy clearly is active in head and neck cancer, both virally related/not related and heavily pre-treated patients. Head and neck cancer shows a prominent immune phenotype. Response rates are reasonable, but they are probably underestimating benefit, impact on survival is significant in responders. Anti-PD-1 and PD-L1 agents are well tolerated but awareness of potential immune-related AEs is important. We still need robust and consistent biomarkers. From KEYNOTE studies, we should carefully select patients avoiding those with HPV negative and PD-L1 negative tumors.

Improvement in quality of life is reported compared with chemotherapy. Combination approaches are promising, first-line combinations studies are ongoing. It is important to learn how to integrate immunotherapy with other treatments. We should argue that, in the near future, the fastest run to register all combinations will probably determine the willingness to use (if economically allowed in any center) many combinations but without a personalized medicine. The cancer immunogram by Blank et al. [16] might suggest, if combinations are needed, which one is preferable, deserving a combination to patients without significant immune cell infiltration and absence of soluble inhibitors. New options for treatment in these patients will be soon available; we should have the ability to select them and to build a flowchart.

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