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Identification of tumours harbouring an overall active immune phenotype may help for selecting patients with advanced head and neck squamous cell carcinomas (HNSCC) and non-small cell lung cancer (NSCLC) who may benefit from immunotherapies. Our objective was to develop a reliable and stable scoring system to identify those immunologically active tumours.Using gene expression profiles of 421 HNSCC, we developed a score to identify immunologically active tumours. Validation of the 'HOT' score was done in 40 HNSCC and 992 NSCLC. Stability of the 'HOT' score was tested in paired HNSCC samples from diagnostic biopsies versus surgically resected specimens, untreated versus recurrent samples, and pre-versus post-cetuximab samples in a total of 76 patients. The association between the 'HOT' score with overall survival (OS) and progression-free survival (PFS) was tested in 184 patients with HNSCC or NSCLC treated with PD-1/PD-L1 inhibitors.A 27-gene expression based 'HOT' score was correlated with: (i) PD-L1 and IDO1 expression, (ii) TCD8 infiltrate and (iii) activation of the IFN-γ pathway. The HOT score concordance when comparing diagnostic biopsies and surgically resected specimens was higher than in untreated samples versus recurrent or pre-versus post-cetuximab samples. In 102 and 82 patients with HNSCC or NSCLC treated with PD-1/PD-L1 inhibitors, the HOT score was associated with an improved OS and PFS in multivariate analysis.The 'HOT' score is a simple and robust approach to identify real-world patients with HNSCC and NSCLC immunologically active tumours who may benefit from PD-1/PD-L1 inhibitors.

Background: Hyperprogressive disease (HPD) rate in head and neck squamous cell carcinoma (HNSCC) patients treated with immune checkpoint inhibitors (ICI) was determined using tumor growth kinetics (TGK) and compared with rapidly progressive screen-failure (SF) patients. The impact of TGK on outcomes with salvage chemotherapy (SCT) was also evaluated. Results: HPD was found in 22/120 (18%) patients. Median TGK before the onset of immunotherapy (TGKpre) was 2.7 for SF patients and 4.8 for HPD patients, with no significant difference (p = 0.17). Disease control rate after initial progressive disease on ICI was 86% with SCT in case of tumor growth deceleration vs 39% in case of tumor growth acceleration. Conclusions: HPD was frequent, but TGK of HPD patients treated with ICI did not differ from SF patients, suggesting that there is no relevant causal relationship between HPD and ICI. After initial PD with ICI, tumor growth deceleration was associated with better outcomes, indicating that TGKR might be useful to detect late responders, meriting prospective investigations. Materials and Methods: TGK ratio (TGKR) was defined as the ratio of TGK on ICI (TGKpost) to TGKpre. HPD was defined as TGKR ≥ 2. TGKR >1 indicated tumor growth acceleration, while 0 < TGKR < 1 indicated tumor deceleration.

Although the mitogen-activated protein kinases (MAPK) pathway is hyperactive in head and neck cancer (HNC), inhibition of MEK1/2 in HNC patients has not shown clinically meaningful activity. Using pre-clinical HNC models, we demonstrated that treatment with the MEK1/2 blocker trametinib delays HNC initiation and progression by reducing tumor cell proliferation and enhancing the anti-tumor immunity of CD8+T cells. Further activation of CD8+T cells by supplementation with anti-programmed death-1 (αPD-1) antibody eliminated tumors and induced an immune memory in the cured mice. Mechanistically, an early response to trametinib treatment sensitized tumors to αPD-1-supplementation by attenuating the expression of tumor-derived colony-stimulating factor-1 (CSF-1), which reduced the abundance of two CSF-1R+CD11c+myeloid-derived suppressor cell (MDSC) populations in the tumor microenvironment (TME). In contrast, prolonged treatment with trametinib abolished the anti-tumor activity of αPD-1, because tumor cells undergoing the epithelial to mesenchymal transition (EMT) in response to trametinib restored CSF-1 expression and re-created an immune-suppressive TME. These findings provide the rationale for testing the trametinib/αPD-1 combination in HNC and highlight the importance of sensitizing tumors to immunotherapies by using targeted therapies to interfere with the host-tumor interaction.Graphical abstract

Resume La vague de l’immunotherapie n’epargne pas les cancers de la tete et du cou. En situation de recidive locale ou metastatique, des inhibiteurs de checkpoint (anti-PD-1/PD-L1) ont l’AMM en deuxieme ligne avec un benefice net, tant en survie globale qu’en qualite de vie. Nombre d’etudes sont en cours, en situation palliative, mais aussi curative, en association ou non avec d’autres inhibiteurs de checkpoint (anti-CTLA4) ou avec des therapies validees (radiotherapie, chimiotherapie). Il est necessaire de definir des biomarqueurs robustes permettant de selectionner efficacement les patients eligibles. En effet, le risque d’effet indesirable grave n’etant pas negligeable, l’enjeu est la selection des patients chez qui l’immunotherapie aura le plus de benefices. Nous ferons ici le point sur l’etat des connaissances en 2018 de l’immunotherapie dans les cancers epidermoides ORL.

Background Programmed death-ligand 1 (PD-L1) is the most validated predictive biomarker used for the treatment of head and neck squamous cell carcinoma (HNSCC) with immune checkpoint inhibitors (ICI). Several gene expression-based signatures surrogate of the activation of IFN-gamma pathway and of the presence of tertiary lymphoid structures (TLS) have also been proposed as potential biomarkers. While they may have a potential therapeutic implication, the longitudinal changes of either PD-L1 or gene expression profiles between the initial and recurrent HNSCC lesions is unknown. Methods PD-L1 immunohistochemistry (IHC) and targeted RNA-sequencing of 2,549 transcripts were analyzed on paired specimens from the initial diagnosis and recurrent HNSCC. PD-L1 status was defined using the combined positive score (CPS). PD-L1 mRNA levels were compared with protein expression levels by IHC. Enrichment scores of surrogate signatures for TLS and IFN-gamma (IFN-γ) pathway activation were computed using the single sample gene set enrichment analysis (ssGSEA). Results PD-L1 status was 64% (21/33) concordant between the initial and recurrent lesions using a CPS 1 threshold and 67% (22/33) concordant using a CPS 20 threshold. CPS score was associated with PD-L1 gene expression levels. There was a 43% (15/35) and 66% (23/35) concordance for the IFN-γ and TLS signature scores, respectively. Conclusion Our study reveals temporal heterogeneity of PD-L1 status and TLS/IFN-γ gene expression surrogates in HNSCC that need to be considered when interpreting biomarker studies.

BackgroundAlthough the mitogen-activated protein kinases (MAPK) pathway is hyperactive in head and neck cancer (HNC), inhibition of MEK1/2 in HNC patients has not shown clinically meaningful activity. Therefore, we aimed to characterize the effect of MEK1/2 inhibition on the tumor microenvironment (TME) of MAPK-driven HNC, elucidate tumor-host interaction mechanisms facilitating immune escape on treatment, and apply rationale-based therapy combination immunotherapy and MEK1/2 inhibitor to induce tumor clearance.MethodsMouse syngeneic tumors and xenografts experiments were used to analyze tumor growth in vivo. Single-cell cytometry by time of flight, flow cytometry, and tissue stainings were used to profile the TME in response to trametinib (MEK1/2 inhibitor). Co-culture of myeloid-derived suppressor cells (MDSC) with CD8+T cells was used to measure immune suppression. Overexpression of colony-stimulating factor-1 (CSF-1) in tumor cells was used to show the effect of tumor-derived CSF-1 on sensitivity to trametinib and anti-programmed death- 1 (αPD-1) in mice. In HNC patients, the ratio between CSF-1 and CD8A was measured to test the association with clinical benefit to αPD-1 and αPD-L1 treatment.ResultsUsing preclinical HNC models, we demonstrated that treatment with trametinib delays HNC initiation and progression by reducing tumor cell proliferation and enhancing the antitumor immunity of CD8+T cells. Activation of CD8+T cells by supplementation with αPD-1 antibody eliminated tumors and induced an immune memory in the cured mice. Mechanistically, an early response to trametinib treatment sensitized tumors to αPD-1-supplementation by attenuating the expression of tumor-derived CSF-1, which reduced the abundance of two CSF-1R+CD11c+MDSC populations in the TME. In contrast, prolonged treatment with trametinib abolished the antitumor activity of αPD-1, because tumor cells undergoing the epithelial to mesenchymal transition in response to trametinib restored CSF-1 expression and recreated an immune-suppressive TME.ConclusionOur findings provide the rationale for testing the trametinib/αPD-1 combination in HNC and highlight the importance of sensitizing tumors to αPD-1 by using MEK1/2 to interfere with the tumor–host interaction. Moreover, we describe the concept that treatment of cancer with a targeted therapy transiently induces an immune-active microenvironment, and supplementation of immunotherapy during this time further activates the antitumor machinery to cause tumor elimination.

Standard treatment for locally advanced head and neck squamous cell carcinoma (LAHNSCC) consists mainly of concurrent chemoradiation (CCR) but induction chemotherapy (IC) by docetaxel-cisplatin-fluorouracil (TPF), followed by CCR, is a strong option. Comparative trials suggest that IC and CCR are equivalent, and some trials suggest superiority of IC, whereas none shows inferiority. IC might have less interest in oropharyngeal cancer (more often linked to HPV infection). When functional laryngeal preservation is the patient's priority, essays strongly suggest that IC is the best treatment. There is little data about a less toxic regimen of IC, but several schemes are promising and need to be developed. An early selection of responders to IC by metabolic imaging must be considered. Intensification attempts with cetuximab were too toxic and unsafe, but trials with immunotherapy are ongoing to enhance TPF efficacy. After IC, CCR either with cetuximab or cisplatin seems to be equally effective.

The immunotherapy revolution has not spared Head and neck squamous cell carcinoma (HNSCC). Checkpoint inhibitors (anti-PD-1 / PD-L1) were the first to be validated in second line treatment and soon come to the first line in local or metastatic recurrence. Many studies are currently underway to expand the indications of these new therapies, whether as monotherapy or in combination. In addition, immunotherapy is not limited to checkpoint inhibitors and many other immunotherapy molecules are currently under study. The selection of patients who benefit from immunotherapy and the evaluation of the response to these treatments are problems not completely solved. The aim here is to present the state of art on immunotherapy in HNSCC.

Induction chemotherapy (IC) in locally advanced head and neck squamous cell carcinoma (LA HNSCC) has been used for decades. However, its role is yet to be clearly defined outside of larynx preservation. Patients with high risk of distant failure might potentially benefit from sequential treatment. It is now widely accepted that TPF (docetaxel, cisplatin, and fluorouracil) is the standard IC regimen. Essays that have compared this approach with the standard of care, concurrent chemoradiotherapy (CCRT), are mostly inconclusive. Radiotherapy (RT) can be used in the post-IC setting and be sensitized by chemotherapy or cetuximab. Again, no consensus exists but there seems to be trend in favor of potentiation by cisplatin. Less toxic schemes of IC are tested as toxicity is a major issue with TPF. IC might have an interesting role in human papilloma virus (HPV)-related LA HNSCC and lead to CCRT de-escalation.

The standard first-line treatment in recurrent/metastatic head and neck squamous cell carcinoma combines Cisplatin, 5 Fluorouracil and Cetuximab, but many patients aren't eligible. We retrospectively evaluated the efficacy and the tolerability of Carboplatin and Paclitaxel in this indication, mostly in patients unfit to Cisplatin. Paclitaxel (80mg/m2) was administered at day 1, 8 and 15 and Carboplatin area under the curve 5 at day 1, repeated every 28 days, for 6 cycles. Carboplatin could be administered at area under the curve 2 at day 1, 8 and 15. 117 patients received this association at our institution, 94 of those were ineligible to cisplatin due to severe comorbidities, age >70years or Performance status >1. The overall response rate was 40%. The median progression free survival for patients ineligible to Cisplatin was 4.4 months [95% CI; 3.4; 5.0] and the median overall survival was 8 months [95% CI; 5.4-10.7]. The most frequent toxicities were hematologic, with 94 grade ≥ 3, mostly in patients who received monthly Carboplatin. Our study shows Carboplatin and Paclitaxel in first-line in recurrent/metastatic head and neck squamous cell carcinoma appear efficient for patients ineligible to Cisplatin and safe when both drugs are weekly administered.

Head and neck cancer is an immunosuppressive disease, with a high proportion expressing PD-L1. Until recently, options were lacking in second line. Prognosis is poor especially for patients who progress during chemotherapy with survival often inferior to 6 months. Nivolumab is the only anti-PD-1 agent to prolong survival in the second-line setting and is now the standard option since the CheckMate-141 trial. Treatment is generally well tolerated, patients seem to have a better quality of life when compared with chemotherapy. Markers of efficacy are lacking even if some data are emerging. Different combinations of immunotherapy are ongoing. Hyperprogression is a phenomenon associated with poor outcome and might be the consequence of anti-PD-1 treatment but this is yet to be proven.

Chemotherapy is the only option of treatment for most patients presenting with a recurrent and/or metastatic head and neck squamous cell carcinoma. The triple association of cisplatin, 5-fluorouracile, and cetuximab is still the current standard for fit patients. Other schemes are currently being compared with this protocol in ongoing trials and the association of cisplatin, docetaxel, and cetuximab appears to be the most efficient. The human papilloma virus is very likely a favorable prognostic factor. Immunotherapy with nivolumab or pembrolizumab is now a new standard of treatment in second line after yielding an improvement in overall survival, but predictive markers of efficacy are needed to refine the selection of patients. The combination of paclitaxel and buparlisib appears to be promising.

Pembrolizumab and nivolumab are immune checkpoint inhibitors targeting PD-1 that have recently been approved in pretreated recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC) patients. In the clinic, some patients seem not only not to benefit from anti-PD-L1/PD-1 agents but rather to experience an acceleration of tumor growth kinetics (TGK).We retrospectively compared TGK on immunotherapy and TGK on last treatment in patients with R/M HNSCC treated with PD-1/PD-L1 inhibitors in four French centers. The TGK ratio (TGKR, ratio of the slope of tumor growth before treatment and the slope of tumor growth on treatment) was calculated. Hyperprogression was defined as a TGKR ≥ 2.From September 2012 to September 2015, 34 patients were identified. Patterns of recurrence included exclusive loco-regional recurrence in 14 patients, exclusive distant metastases in 11 patients, and both in 9 patients. No pseudo-progression was observed. Hyperprogression was observed in 10 patients (29%), including 9 patients with at least a locoregional recurrence, and only 1 patient with exclusively distant metastases. Hyperprogression significantly correlated with a regional recurrence (TGKR ≥ 2: 90% versus TGKR2: 37%, P = 0.008), but not with local or distant recurrence. Hyperprogression was associated with a shorter progression-free survival (PFS) according to RECIST (P = 0.003) and irRECIST (P = 0.02), but not with overall survival (P = 0.77).Hyperprogression was observed in 29% of patients with R/M HNSCC treated with anti-PD-L1/PD-1 agents and correlated with a shorter PFS. It occurred in 39% of patients with at least a locoregional recurrence and 9% of patients with exclusively distant metastases. No pseudo-progressions were reported. Mechanisms and causality of hyperprogression should further be assessed through prospective controlled studies.