Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial

Seiwert, Tanguy Y.; Burtness, Barbara; Mehra, Ranee; Weiss, Jared; Berger, Raanan; Eder, Joseph P.; Heath, Karl; McClanahan, Terrill K.; Lunceford, Jared; Gause, Christine K.; Cheng, Jonathan D.; Chow, Laura Q.M.

doi:10.1016/s1470-2045(16)30066-3

Cited by 1,386 publications

(1,276 citation statements)

References 27 publications

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“…Immunotherapy using antibodies targeting checkpoint proteins has become of increasing interest and a number of clinical trials using these antibodies for several different cancer types have shown clinical responses 22, 23, 24, 25, 26, 27, 28. However, studies with animal models and cancer patients have also shown that combining antibody blockade of the PD‐1/PD‐L1 axis with other forms of immunotherapy can lead to more meaningful clinical responses 32, 33, 34, 35.…”

Section: Discussionmentioning

confidence: 99%

“…Studies involving patients with advanced melanoma showed clinical effectiveness of treatment with the anti‐PD‐1 antibody pembrolizumab 22, 23. In a trial involving recurrent or metastatic HNSCC patients for whom there were few treatment options, pembrolizumab was manageably tolerated and demonstrated clinical effectiveness, particularly in subjects with PD‐L1‐positive tumors 24. Similarly, pembrolizumab treatment of patients with PD‐L1‐positive advanced non‐small‐cell lung cancer prolonged their overall survival 25.…”

Section: Introductionmentioning

confidence: 99%

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Transient immunological and clinical effectiveness of treating mice bearing premalignant oral lesions with PD‐1 antibodies

Levingston

Young

2017

Intl Journal of Cancer

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A carcinogen‐induced premalignant oral lesion model that progresses to oral cancer was used to examine the impact of blocking PD‐1 on cytokine expression and on progression of lesions to cancer. The results of this study show increased production of IL‐2 and the inflammatory cytokines IL‐6, IL‐17 and TNF‐α by spleen cells of lesion‐bearing mice that were treated with PD‐1 antibody for 1 week compared to cytokine production by spleen cells of lesion‐bearing mice treated with control antibody. Production of IFN‐γ increased at 3 weeks of PD‐1 antibody treatment, although production of the other Th1 and inflammatory mediators declined. By 5 weeks, levels of these cytokines declined for both control and PD‐1 antibody‐treated mice. Flow cytometric analysis for IFN‐γ‐expressing cells showed shifts in CD4+ cells expressing IFN‐γ consistent with the changes in cytokine secretion. Whether or not treatment generated reactivity to lesions or HNSCC was determined. Spleen cells from PD‐1 antibody‐treated mice were stimulated by lysates of premalignant lesion and HNSCC tongue tissues to produce increased levels of Th1 and select inflammatory cytokines early in the course of PD‐1 antibody treatment. However, with continued treatment, reactivity to lesion and HNSCC lysates declined. Analysis of clinical response to treatment suggested an early delay in lesion progression but, with continued treatment, lesions in PD‐1 antibody‐treated mice progressed to the same degree as in control antibody‐treated mice. Overall, these results show an early beneficial response to PD‐1 antibody treatment, which then fails with continued treatment and lesion progression.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Transient immunological and clinical effectiveness of treating mice bearing premalignant oral lesions with PD‐1 antibodies

Levingston

Young

2017

Intl Journal of Cancer

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“…Thus, we computed the enrichment score of a six-gene response signature to pembrolizumab in HNSCC [14], in the four independent cohorts ( Figure 3C). Interestingly, scores were higher in NSND compared to SD in TCGA (P=0.0012); GEO1 (P=0.0271); GEO2 (P=0.0181) and CLB cohorts (P=0.0002).…”

Section: The Main Biological Difference Between Oscc From Nsnd and Sdmentioning

confidence: 99%

The immune microenvironment of HPV-negative oral squamous cell carcinoma from never-smokers and never-drinkers patients suggests higher clinical benefit of IDO1 and PD1/PD-L1 blockade

et al. 2017

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To cite this version:P. Foy, Chloé Bertolus, Marie-Cécile Michallet, Sophie Deneuve, R. Incitti, et al.. The immune microenvironment of HPV-negative oral squamous cell carcinoma from never-smokers and never-drinkers patients suggests higher clinical benefit of IDO1 and PD1/PD-L1 blockade. Annals of Oncology, Oxford University Press (OUP), 2017, 28 (8), pp.1934-1941 Background: Never-smokers and never-drinkers patients (NSND) suffering from oral

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“…41 Overall, the interaction between the immune system and neoplasia reflects a fundamental principle, applicable to all organ/cell types. 42 The recent success of the use of PD-1 immune checkpoint blockade in advanced HNSCC 43–45 confirms the clinical importance of immune modulation in this context. Overall, tumors orchestrate a complex signaling network to induce immune tolerance.…”

Section: Discussionmentioning

confidence: 89%

Immunological and classical subtypes of oral premalignant lesions

et al. 2018

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Oral squamous cell carcinoma (OSCC) is a major cause of cancer-associated morbidity and mortality and may develop from oral premalignant lesions (OPL). An improved molecular classification of OPL may help refining prevention strategies. We identified two main OPL gene-expression subtypes, named immunological and classical, in 86 OPL (discovery dataset). A gene expression-based score was then developed to classify OPL samples from three independent datasets, including 17 (GSE30784),13 (GSE10174) and 15 (GSE85195) OPLs, into either one of the two gene-expression subtypes. Using the single sample gene set enrichment analysis, enrichment scores for immune-related pathways were different between the two OPL subtypes. In OPL from the discovery set, loss of heterozygosities (LOH) at 3p14, 17p13, TP53, 9p21 and 8p22 and miRNA gene expression profiles were analyzed. Deconvolution of the immune infiltrate was performed using the Microenvironment Cell Populations-counter tool. A multivariate analysis revealed that decreased miRNA-142-5p expression (P = 0.0484) and lower T-cell, monocytic and myeloid dendritic cells (MDC) immune infiltration (T-cells, P = 0.0196; CD8 T cells, P = 0.0129; MDC, P = 0.0481; and monocytes, P = 0.0212) were associated with oral cancer development in the immunological subtype only. In contrast, LOH at 3p14 (P = 0.0241), 17p13 (P = 0.0348) and TP53 (P = 0.004) were associated with oral cancer development in the classical subtype only. In conclusion, we identified 2 subtypes of OPLs, namely immune and classical, which may benefit from different and specific personalized prevention interventions.

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Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial

Cited by 1,386 publications

References 27 publications

Transient immunological and clinical effectiveness of treating mice bearing premalignant oral lesions with PD‐1 antibodies

Transient immunological and clinical effectiveness of treating mice bearing premalignant oral lesions with PD‐1 antibodies

The immune microenvironment of HPV-negative oral squamous cell carcinoma from never-smokers and never-drinkers patients suggests higher clinical benefit of IDO1 and PD1/PD-L1 blockade

Immunological and classical subtypes of oral premalignant lesions

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