Dual blockade of programmed death ligand 1 (PD-L1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) may overcome immune checkpoint inhibition. It is unknown whether dual blockade can ...potentiate antitumor activity without compromising safety in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) and low or no PD-L1 tumor cell expression.
To assess safety and objective response rate of durvalumab combined with tremelimumab.
The CONDOR study was a phase 2, randomized, open-label study of Durvalumab, Tremelimumab, and Durvalumab in Combination With Tremelimumab in Patients With R/M HNSCC. Eligibility criteria included PD-L1-low/negative disease that had progressed after 1 platinum-containing regimen in the R/M setting. Patients were randomized (N = 267) from April 15, 2015, to March 16, 2016, at 127 sites in North America, Europe, and Asia Pacific.
Durvalumab (20 mg/kg every 4 weeks) + tremelimumab (1 mg/kg every 4 weeks) for 4 cycles, followed by durvalumab (10 mg/kg every 2 weeks), or durvalumab (10 mg/kg every 2 weeks) monotherapy, or tremelimumab (10 mg/kg every 4 weeks for 7 doses then every 12 weeks for 2 doses) monotherapy.
Safety and tolerability and efficacy measured by objective response rate.
Among the 267 patients (220 men 82.4%), median age (range) of patients was 61.0 (23-82) years. Grade 3/4 treatment-related adverse events occurred in 21 patients (15.8%) treated with durvalumab + tremelimumab, 8 (12.3%) treated with durvalumab, and 11 (16.9%) treated with tremelimumab. Grade 3/4 immune-mediated adverse events occurred in 8 patients (6.0%) in the combination arm only. Objective response rate (95% CI) was 7.8% (3.78%-13.79%) in the combination arm (n = 129), 9.2% (3.46%-19.02%) for durvalumab monotherapy (n = 65), and 1.6% (0.04%-8.53%) for tremelimumab monotherapy (n = 63); median overall survival (95% CI) for all patients treated was 7.6 (4.9-10.6), 6.0 (4.0-11.3), and 5.5 (3.9-7.0) months, respectively.
In patients with R/M HNSCC and low or no PD-L1 tumor cell expression, all 3 regimens exhibited a manageable toxicity profile. Durvalumab and durvalumab + tremelimumab resulted in clinical benefit, with minimal observed difference between the two. A phase 3 study is under way.
clinicaltrials.gov Identifier: NCT02319044.
Over the past 10 years, cancer immunotherapy has made significant progress in multiple cancer types and has been gradually been applied to clinical cancer care, in which the programmed cell death ...protein-1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway is one of the most attractive targets. Compared with traditional therapies, the emerging PD-1/PD-L1 blockade immunotherapy exhibited more satisfactory curative effects and lower toxicity for patients with advanced head and neck squamous cell carcinoma (HNSCC). This review analyzes the expression characteristics and clinical significance of PD-1/PD-L1 in HNSCC, the immunosuppressive roles of tumor cell and stromal cell expressing PD-1/PD-L1 in this disease, and presents the development landscape of PD-1/PD-L1 inhibitors, which may provide new curative alternatives for recurrent or metastatic HNSCC.
The onerous health and economic burden associated with head and neck squamous cell carcinoma (HNSCC) is a global predicament. Despite the advent of novel surgical techniques and therapeutic ...protocols, there is an incessant need for efficacious diagnostic and therapeutic targets to monitor the invasion, metastasis and recurrence of HNSCC due to its substantial morbidity and mortality. The differential expression patterns of histone deacetylases (HDACs), a group of enzymes responsible for modifying histones and regulating gene expression, have been demonstrated in neoplastic tissues. However, there is limited knowledge regarding the role of HDACs in HNSCC. Consequently, this review aims to summarize the existing research findings and explore the potential association between HDACs and HNSCC, offering fresh perspectives on therapeutic approaches targeting HDACs that could potentially enhance the efficacy of HNSCC treatment. Additionally, the Cancer Genome Atlas (TCGA) dataset, CPTAC, HPA, OmicShare, GeneMANIA and STRING databases are utilized to provide supplementary evidence on the differential expression of HDACs, their prognostic significance and predicting functions in HNSCC patients.
We aimed to investigate the prognostic value of tumour-infiltrating lymphocytes' (TILs) expression in pretreatment specimens from patients with head and neck squamous cell carcinoma (HNSCC) treated ...with definitive chemoradiotherapy (CRT).
The prevalence of CD3+, CD8+, CD4+ and FOXP3+ TILs was assessed using immunohistochemistry in tumour tissue obtained from 101 patients before CRT and was correlated with clinicopathological characteristics as well as local failure-free- (LFFS), distant metastases free- (DMFS), progression-free (PFS) and overall survival (OS). Survival curves were measured using the Kaplan-Meier method, and differences in survival between the groups were estimated using the log-rank test. Prognostic effects of TIL subset density were determined using the Cox regression analysis.
With a mean follow-up of 25 months (range, 2.3-63 months), OS at 2 years was 57.4% for the entire cohort. Patients with high immunohistochemical CD3 and CD8 expression had significantly increased OS (P=0.024 and P=0.028), PFS (P=0.044 and P=0.047) and DMFS (P=0.021 and P=0.026) but not LFFS (P=0.90 and P=0.104) in multivariate analysis that included predictive clinicopathologic factors, such as age, sex, T-stage, N-stage, tumour grading and localisation. Neither CD4 nor FOXP3 expression showed significance for the clinical outcome. The lower N-stage was associated with improved OS in the multivariate analysis (P=0.049).
The positive correlation between a high number of infiltrating CD3+ and CD8+ cells and clinical outcome indicates that TILs may have a beneficial role in HNSCC patients and may serve as a biomarker to identify patients likely to benefit from definitive CRT.
High-risk Human Papillomavirus (HPV) infections have recently emerged as an independent risk factor in head and neck squamous cell carcinoma (HNSCC). There has been a marked increase in the incidence ...of HPV-induced HNSCC subtype, which demonstrates different genetics with better treatment outcome. Despite the favourable prognosis of HPV-HNSCC, the treatment modality, consisting of high dose radiotherapy (RT) in combination with chemotherapy (CT), remains similar to HPV-negative tumours, associated with toxic side effects. Epidermal growth factor receptor (EGFR) is overexpressed in over 80% of HNSCC and correlates with RT resistance. EGFR inhibitor Cetuximab is the only FDA approved targeted therapy for both HNSCC subtypes, however the response varies between HNSCC subtypes. In HPV-negative HNSCC, Cetuximab sensitises HNSCC to RT improving survival rates. To reduce adverse cytotoxicity of CT, Cetuximab has been approved for treatment de-escalation of HPV-positive HNSCC. The results of several recent clinical trials have concluded differing outcome to HPV-negative HNSCC. Here we investigated the role of EGFR in HPV-positive HNSCC response to RT. Remarkably, in HPV-positive HNSCC cell lines and in vivo tumour models, EGFR activation was strongly indicative of increased RT response. In response to RT, EGFR activation induced impairment of DNA damage repair and increased RT response. Furthermore, EGFR was found to downregulate HPV oncoproteinE6 expression and induced p53 activity in response to RT. Collectively, our data uncovers a novel role for EGFR in virally induced HNSCC and highlights the importance of using EGFR-targeted therapies in the context of the genetic makeup of cancer.
•EGFR activation is strongly correlated with worse survival outcome and radiotherapy resistance in HNSCC.•HPV-positive HNSCC patients showed inferior outcomes when treated with Cetuximab, the only FDA-approved targeted agent for HNSCC.•EGFR activation in HPV-positive HNSCC cell lines induced clear radiosensitisation in mice.•EGFR overexpression inhibited DNA damage repair , suppressed HPV-E6, restorating p53 activity and increased radiotherapy response.•EGFR function differs in HPV---derived HNSCC subtype, which needs to be considered in using EGFR targeted therapies for treating head and neck cancer patients.
Surgery often represents the best chance for disease control in locoregionally recurrent squamous cell carcinoma of the head and neck (SCCHN). We investigated dual immune-checkpoint inhibition ...anti-PD-1, nivolumab (N), and anti-KIR, lirilumab (L) before and after salvage surgery to improve disease-free survival (DFS).
In this phase II study, patients received N (240 mg) + L (240 mg) 7 to 21 days before surgery, followed by six cycles of adjuvant N + L. Primary endpoint was 1-year DFS; secondary endpoints were safety, pre-op radiologic response, and overall survival (OS). Correlatives included tumor sequencing, PD-L1 scoring, and immunoprofiling.
Among 28 patients, the median age was 66, 86% were smokers; primary site: 9 oral cavity, 9 oropharynx, and 10 larynx/hypopharynx; 96% had prior radiation. There were no delays to surgery. Grade 3+ adverse events: 11%. At the time of surgery, 96% had stable disease radiologically, one had progression. Pathologic response to N + L was observed in 43% (12/28): 4/28 (14%) major (tumor viability, TV ≤ 10%) and 8/28 (29%) partial (TV ≤ 50%). PD-L1 combined positive score (CPS) at surgery was similar regardless of pathologic response (
= 0.71). Thirteen (46%) recurred (loco-regional = 10, distant = 3). Five of 28 (18%) had positive margins, 4 later recurred. At median follow-up of 22.8 months, 1-year DFS was 55.2% (95% CI, 34.8-71.7) and 1-year OS was 85.7% (95% CI, 66.3-94.4). Two-year DFS and OS were 64% and 80% among pathologic responders.
(Neo)adjuvant N + L was well tolerated, with a 43% pathologic response rate. We observed favorable DFS and excellent 2-year OS among high-risk, previously treated patients exhibiting a pathologic response. Further evaluation of this strategy is warranted.
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Patients with immunosuppression have a higher incidence of cutaneous squamous cell carcinoma (cSCC) and often present with more aggressive, multifocal disease.
To determine the risks for mortality in ...patients with cSCC and immunosuppression compared with nonimmunosuppression and to compare the difference in mortality risk based on the cause of immunocompromise.
This retrospective cohort study of patients with cSCC of the head and neck recruited participants from a tertiary cancer care center. Patients who underwent no treatment, wide local excision, or biopsy of the lesions were eligible for inclusion from January 1, 1995, to September 30, 2015. Data were analyzed from March 21, 2018, to April 4, 2019.
Immunocompromise, defined as having solid organ transplant, stem cell transplant, hematopoetic malignant disease, autoimmune disease requiring treatment with immunosuppressive therapy, type 1 or 2 diabetes treated with insulin, HIV or AIDS, or other hematoproliferative disorder.
Patients were divided into 2 groups according to their immune status (immunosuppression vs no immunosuppression). The primary outcome measure was disease-specific survival. A Cox proportional hazards regression model was used to determine the association of immune status with disease outcome.
A total of 796 patients (680 men 85.4%; median age, 69 range, 27-98 years), including 147 with and 649 without immunosuppression (IS and non-IS groups, respectively), constituted the final cohort. In the IS group, 77 (52.4%) had diabetes, 39 (26.5%) had lymphoma or leukemia, 25 (17.0%) had an organ or stem cell transplant, and 3 (2.0%) had HIV. Five-year disease-specific survival was 68.2% in the IS group compared with 84.1% in the non-IS group (difference, 15.9%; 95% CI, 3.5%-27.4%). Immunosuppression was independently associated with worse disease-specific survival (hazard ratio, 2.32; 95% CI, 1.53-3.50).
This study's findings suggest that immunosuppression is independently associated with a worse outcome in cSCC, with a 2.32 times increased risk of disease-specific death after adjusting for age, history of skin cancer, recurrent or persistent disease status, disease stage, and treatment.
Radiation is a crucial component of head and neck squamous cell carcinoma (HNSC) treatment. Human papillomavirus-positive (HPV+) HNSC is significantly more radiosensitive than HPV- HNSC, but the ...mechanism underlying this increased sensitivity is unknown. We investigated the possible involvement of macrophage subpopulations as key mediators of HNSC radiosensitivity linked to HPV status. We collected forty-one clinical HNSC specimens and determined HPV status and radiosensitivity of each sample. We investigated cytokine mediated induction of macrophage polarization by HPV+ and HPV- HNSC cells. Radiosensitive HNSC tissues exhibited greater numbers of infiltrating M1 macrophages than radioresistant tumor tissue samples. Moreover, M1 macrophage numbers were positively correlated with HNSC radiosensitivity. HPV+ and HPV− tumor cells induced macrophage polarization to M1 and M2 type, respectively. HPV+ HNSC cells secreted more IL-6 than HPV− cells. HPV promoted tumor cell secretion of IL-6, thereby increasing radiosensitivity through M1 polarization of macrophages. M1 macrophages represent an important tissue microenvironment factor with implications for HNSC treatment efficacy and may prove valuable as a biomarker of radiation sensitivity.
•Radiosensitive HNSC tissues exhibited greater numbers of infiltrating M1 macrophages than radioresistant tumor tissues.•M1 macrophage numbers were positively correlated with HNSC radiosensitivity.•HPV+ and HPV- tumor cells could induce macrophage polarization to M1 and M2 type, respectively.•HPV promoted tumor cell secretion of IL-6, thereby inducing M1 polarization of macrophages.
Background
No predictive biomarker of immune checkpoint inhibitors in head and neck squamous cell carcinoma (HNSCC) has been well established. The impact of programmed death-ligand 1 (PD-L1) ...expression, CD8+ tumor-infiltrating lymphocytes (TILs), and p16 status in HNSCC is unclear and may vary according to ethnicity.
Methods
HNSCC patients treated between 2007 and 2013 were reviewed. Archival tissues were retrieved for PD-L1, CD8+ TILs, and p16 analyses. PD-L1 expression was evaluated by using the validated SP142 assay on the VENTANA platform. CD8+ TILs were defined by using semiquantitative scoring.
Results
A total of 203 patients were analyzed. PD-L1 expression was observed in 80% of patients and was significantly associated with older age (
P
< 0.001). A high CD8+ TIL score (≥ 6) was significantly associated with never-smoking (
P
= 0.020), oral cavity cancer (
P
< 0.001), and stage M0 at presentation (
P
= 0.025). The p16 status was positive in 12% of patients. Patients with a high TIL score had a significantly longer OS (
P
= 0.032). Patients with PD-L1 expression of 1–49% and ≥ 50% were associated with a significantly shorter OS compared with those with PD-L1 < 1% (
P
= 0.027 and
P
= 0.011, respectively). Multivariate analysis showed that PD-L1 ≥ 50% was significantly associated with a poor OS. (HR 2.98 95% CI 1.2–7.39;
P
= 0.019.)
Conclusions
A high prevalence of PD-L1 expression was observed in HNSCC using the validated SP142 assay. PD-L1 expression was associated with older age, while highly PD-L1 expression (≥ 50%) was an independent prognostic factor for poor OS in anti-PD1/PD-L1 untreated HNSCC patients.
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