p16 immunocytochemistry on aspirate smears of neck masses: Another option for determining the HPV status in metastatic head and neck squamous cell carcinoma

HPV-related head and neck squamous cell carcinoma (HNSCC) has emerged as a diverse clinical and biological disease entity, mainly in young patients with oropharyngeal tumors who are nonsmokers and nondrinkers. Indeed, during the past few years, the pendulum has shifted towards a new epidemiological reality, the “HPV pandemic”, where the majority of oropharyngeal squamous cell carcinomas (OPSCCs) are attributed to HPV. The oncogenic potential of the virus is associated to its capacity of integrating oncogenes E6 and E7 into the host cell, leading to the inactivation of several tumor suppressor genes, such as Rb. HPV status can affect prognosis in OPSCC, but its role as a predictive biomarker remains to be elucidated. Given the favorable prognosis associated with HPV-positive disease, the concept of de-escalation treatment strategies has been developed with the primary intent being the reduction of treatment-related long-term toxicities. In this review, we aim to depict current data regarding treatment de-escalation in HPV-associated OPSCC and discuss ongoing clinical trials.

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PD-031 CT-based Radiomics Predicting HPV Status in Head and Neck Squamous Cell Carcinoma

Radiotherapy and Oncology ◽

10.1016/s0167-8140(19)30197-5 ◽

2019 ◽

Vol 132 ◽

pp. 18-19

Author(s):

Z. Shi ◽

C. Zhang ◽

M. Welch ◽

P. Petros ◽

L. Wee ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Head And Neck ◽

Squamous Cell ◽

Neck Squamous Cell Carcinoma ◽

Hpv Status

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CMP-001-007: Open-label, phase 2 study of intratumoral CMP-001 + pembrolizumab in patients with recurrent or metastatic head and neck squamous cell carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.tps6089 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. TPS6089-TPS6089

Author(s):

Deborah J.L. Wong ◽

Aru Panwar ◽

Ari Rosenberg ◽

Vidhya Karivedu ◽

Douglas Earl Laux ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Head And Neck ◽

Squamous Cell ◽

Systemic Therapy ◽

Neck Squamous Cell Carcinoma ◽

Type I ◽

Open Label ◽

Primary Tumors ◽

Hpv Status

TPS6089 Background: PD-1 blockade ± chemotherapy has recently become a primary systemic therapy recommended by NCCN guidelines for patients (pts) with recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). However, most pts still do not respond to treatment, indicating a large unmet need for pts with unresectable disease. CMP-001 is a toll-like receptor 9 (TLR9) agonist comprising a CpG-A oligodeoxynucleotide packaged in a virus-like particle that can induce type I interferon secretion from tumor-associated plasmacytoid dendritic cells, promoting a Th1-like chemokine milieu in the tumor microenvironment and inducing an antitumor CD8+ T-cell response. In a phase (ph) 1b study in pts with metastatic melanoma, intratumoral (IT) injection of CMP-001 + intravenous (IV) pembrolizumab (pembro) reversed PD-1 blockade resistance, induced responses in injected and noninjected lesions, and had an acceptable safety profile (Milhem et al, SITC 2020). This combination is therefore being tested in pts with HNSCC. Methods: CMP-001-007 (NCT04633278) is an open-label, multicenter, ph 2 study designed to investigate the efficacy and safety of CMP-001 + IV pembro in adult pts with histologically or cytologically confirmed R/M HNSCC considered incurable by local therapies. Eligible pts have undergone a pretreatment tumor biopsy, received no prior systemic therapy in the R/M setting, and have primary tumor locations of oropharynx, oral cavity, hypopharynx, or larynx. In addition, pts must have PD-L1-positive tumors (combined positive score ≥1), known tumor human papillomavirus (HPV) status (for oropharyngeal cancer), and measurable disease per RECIST v1.1 with ≥1 lesion amenable to IT injection. Pts with primary tumors in the nasopharynx are excluded. Enrolled pts will receive CMP-001 10 mg once weekly for 7 doses and every 3 weeks (Q3W) thereafter. The first dose may be administered subcutaneously or via IT injection, with all subsequent doses administered IT. All pts will also receive pembro 200 mg IV Q3W after the CMP-001 injection. Treatment continues until unacceptable toxicity or disease progression. The primary endpoint is investigator-assessed objective response rate (ORR) per RECIST v1.1. Secondary endpoints include safety, duration of response (DOR), progression-free survival (PFS), overall survival, and effects of HPV infection and PD-L1 expression on ORR, DOR, and PFS. Exploratory endpoints include analyses of baseline and changes from baseline in tumor or serum biomarkers related to TLR9, immune checkpoints, and potential predictors of response, as well as serum concentrations of CXCL10 and CMP-001. Refer to clinicaltrials.gov/ct2/show/NCT04633278 for the most current information on enrolling sites. Clinical trial information: NCT04633278.

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Abstract 4372: Genomic, RNAi screening, and functional validation reveal cross activation of classical and alternative NFκB pathways in head and neck squamous cell carcinoma of different HPV status

10.1158/1538-7445.am2017-4372 ◽

2017 ◽

Author(s):

Xinping Yang ◽

Hui Cheng ◽

Ru Wang ◽

Jianhong Chen ◽

Han Si ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Head And Neck ◽

Squamous Cell ◽

Neck Squamous Cell Carcinoma ◽

Functional Validation ◽

Rnai Screening ◽

Hpv Status

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HPV-positive status associated with inflamed immune microenvironment and improved response to anti-PD-1 therapy in head and neck squamous cell carcinoma

Scientific Reports ◽

10.1038/s41598-019-49771-0 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 16

Author(s):

Jian Wang ◽

Hao Sun ◽

Qin Zeng ◽

Xue-Jun Guo ◽

Hui Wang ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

T Cell ◽

Cell Carcinoma ◽

Head And Neck ◽

Squamous Cell ◽

Hpv Infection ◽

Neck Squamous Cell Carcinoma ◽

Integrated Analysis ◽

Immune Microenvironment ◽

Hpv Status

Abstract Chemotherapy and radiotherapy predominantly improve the clinical outcomes of patients with human papillomavirus (HPV)-related head and neck squamous cell carcinoma (HNSCC). Whether this superiority goes on when treated with immune checkpoint inhibitors is still unclear. This study sought to determine the predictive value and potential mechanisms of HPV status for the treatment of programmed cell death 1 (PD-1)/ligand 1(PD-L1) inhibitors. We conducted an integrated analysis of the relationships between HPV status and PD-L1, tumor mutation burden (TMB) and inflammation-related immune cells and molecules, based on the analysis of repository databases and resected HNSCC specimens. The pooled analysis of overall survival (OS) and objective response rate (ORR) suggested that HPV-positive patients benefited more from PD-1/PD-L1 inhibitors than HPV-negative patients (OS: hazard ratio (HR) = 0.71, p = 0.02; ORR: 21.9% vs 14.1%, odds ratio (OR) = 1.79, p = 0.01). Analysis of public databases and resected HNSCC specimens revealed that HPV status was independent of PD-L1 expression and TMB in HNSCC. However, HPV infection significantly increased T-cell infiltration, immune effector cell activation and the diversity of T-cell receptors. Notably, HPV-positivity correlated with increased immune cytolytic activity and a T-cell-inflamed gene expression profile. This work provides evidence that HPV status can be used to predict the effectiveness of PD-1 inhibitors in HNSCC, independently of PD-L1 expression and TMB, and probably results from an inflamed immune microenvironment induced by HPV infection.

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Peripheral Cytokine Levels Differ by HPV Status and Change Treatment-Dependently in Patients with Head and Neck Squamous Cell Carcinoma

International Journal of Molecular Sciences ◽

10.3390/ijms21175990 ◽

2020 ◽

Vol 21 (17) ◽

pp. 5990

Author(s):

Daphne Mytilineos ◽

Jasmin Ezić ◽

Adrian von Witzleben ◽

Joannis Mytilineos ◽

Ramin Lotfi ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Head And Neck ◽

Inflammatory Cytokines ◽

Squamous Cell ◽

Immune Cell ◽

Neck Squamous Cell Carcinoma ◽

Immune Mediators ◽

Radio Therapy ◽

Hpv Status

Cytokines and immune mediators play an important role in the communication between immune cells guiding their response to infectious diseases or cancer. In this study, a comprehensive longitudinal analysis of serum cytokines and immune mediators in head and neck squamous cell carcinoma (HNSCC) patients was performed. In a prospective, non-interventional, longitudinal study, blood samples from 22 HNSCC patients were taken at defined time points (TP) before, during, and every 3 months after completion of (chemo)radio)therapy (CRT/RT) until 12 months after treatment. Serum concentrations of 17 cytokines/immune mediators and High-Mobility-Group-Protein B1 (HMGB1) were measured by fluorescent bead array and ELISA. Concentrations of sFas were significantly elevated during and after CRT/RT, whereas perforin levels were significantly decreased after CRT/RT. Levels of MIP-1β and Granzyme B differed significantly during CRT/RT by HPV status. Increased HMGB1 levels were observed at recurrence, accompanied by high levels of IL-4 and IL-10. The sFas increase and simultaneous perforin decrease may indicate an impaired immune cell function during adjuvant radiotherapy. Increased levels of pro-inflammatory cytokines in HPV+ compared to HPV− patients seem to reflect the elevated immunogenicity of HPV-positive tumors. High levels of HMGB1 and anti-inflammatory cytokines at recurrence may be interpreted as a sign of immune evasion.

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The radiobiology of HPV-positive and HPV-negative head and neck squamous cell carcinoma

Expert Reviews in Molecular Medicine ◽

10.1017/erm.2020.4 ◽

2020 ◽

Vol 22 ◽

Author(s):

Chumin Zhou ◽

Jason L. Parsons

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Head And Neck ◽

Squamous Cell ◽

Survival Rates ◽

Cell Cycle Checkpoint ◽

Neck Squamous Cell Carcinoma ◽

Hpv Status ◽

Hnscc Cell

Abstract Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, with reported incidences of ~800 000 cases each year. One of the critical determinants in patient response to radiotherapy, particularly for oropharyngeal cancers, is human papillomavirus (HPV) status where HPV-positive patients display improved survival rates and outcomes particularly because of increased responsiveness to radiotherapy. The increased radiosensitivity of HPV-positive HNSCC has been largely linked with defects in the signalling and repair of DNA double-strand breaks. Therefore, strategies to further radiosensitise HPV-positive HNSCC, but also radioresistant HPV-negative HNSCC, have focussed on targeting key DNA repair proteins including PARP, DNA-Pk, ATM and ATR. However, inhibitors against CHK1 and WEE1 involved in cell-cycle checkpoint activation have also been investigated as targets for radiosensitisation in HNSCC. These studies, largely conducted using established HNSCC cell lines in vitro, have demonstrated variability in the response dependent on the specific inhibitors and cell models utilised. However, promising results are evident targeting specifically PARP, DNA-Pk, ATR and CHK1 in synergising with radiation in HNSCC cell killing. Nevertheless, these preclinical studies require further expansion and investigation for translational opportunities for the effective treatment of HNSCC in combination with radiotherapy.

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