Search Results (113)

Objective: Sinonasal squamous cell carcinoma (SNSCC) is a rare and aggressive malignancy, with limited treatment strategies in the recurrent or metastatic cases. Although immune checkpoint inhibitors (ICIs) have shown efficacy in head and neck cancers (HNCs), clinical data specific to SNSCC are scarce. This study aimed to evaluate the therapeutic efficacy and prognosis of ICIs in patients with SNSCC. Methods: We conducted a retrospective review of 18 patients with pathologically confirmed SNSCC treated with nivolumab or pembrolizumab at Gifu University Hospital between May 2017 and December 2024. Treatment response was assessed using RECIST v1.1 criteria. Overall response rate (ORR) and disease control rate (DCR) were evaluated as treatment effects, and overall survival (OS) and progression-free survival (PFS) were evaluated as prognoses. Subgroup analyses were performed according to treatment regimen. Results: The ORR and DCR for all patients were 43.8% and 56.3%, respectively. Pembrolizumab-treated patients showed higher response rates (ORR: 66.7%; DCR: 83.3%) compared to those treated with nivolumab (ORR: 30%; DCR: 40%). Median OS and PFS were 21.5 and 7.9 months, respectively. Long-term durable responses exceeding two years were observed in several cases. Although pembrolizumab tended to result in better outcomes, no statistically significant difference was found between groups. Immune-related adverse events were infrequent and manageable. Conclusions: This study suggests that a subset of patients with SNSCC may benefit from ICI therapy, particularly in combination with chemotherapy. Despite the rarity of SNSCC, accumulating clinical evidence—including prospective studies—is essential to establish standardized treatment strategies for this disease. Full article

Head and neck squamous cell carcinoma (HNSCC) is a highly heterogeneous malignancy characterized by a complex tumor microenvironment (TME) that plays a critical role in disease progression and therapeutic resistance. Tumor-infiltrating immune cells, including T lymphocytes, macrophages, dendritic cells, and myeloid-derived suppressor cells, exhibit dual functions, either promoting or suppressing tumor growth depending on their phenotype and interactions within the TME. The presence of immune evasion mechanisms, such as the loss of human leukocyte antigen (HLA) expression, upregulation of immune checkpoint molecules, and metabolic reprogramming (hypoxia-induced glycolysis and lactate accumulation), further contributes to immune suppression and poor treatment responses. While immune checkpoint inhibitors (ICIs) have revolutionized the treatment of recurrent/metastatic HNSCC, response rates remain highly variable, underscoring the need for biomarker-driven patient selection and combinatorial therapeutic strategies. This review provides a comprehensive analysis of the role of immune cells in the TME of HNSCC, discusses the mechanisms underlying immune escape, and explores emerging immunotherapeutic and epigenetic-targeting approaches aimed at enhancing antitumor immune responses and improving clinical outcomes. Full article

Background/Objectives: In recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC), the overall prognosis is poor, and systemic treatment options remain limited. While precision therapy approaches have revolutionized treatment strategies in several tumor types, molecularly informed therapies in R/M HNSCC are rare, primarily due to the low number of actionable genetic alterations identified through next-generation sequencing (NGS) panels. There is an urgent need to establish precision therapy approaches in R/M HNSCC using innovative predictive testing. Methods: We report the case of a 43-year-old patient with recurrent oral cancer who was extensively pretreated and comprehensively characterized using both descriptive and functional testing. Results: NGS revealed no targetable alterations. A tumor tissue slice radiosensitivity assay suggested radioresistance, arguing against re-irradiation. Kinome profiling identified upregulated Src-family kinases (SFK), and SFK inhibition reduced kinase activity in vitro. Most notably, mRNA analysis demonstrated high Trop-2 overexpression, confirmed by immunohistochemistry (3+ in 100% of tumor cells). Following six cycles of the Trop-2-directed antibody–drug conjugate Sacituzumab govitecan (SG), the patient had an impressive clinical response. Conclusions: Tumor characterization beyond genetic profiling can identify novel treatment options in therapy-refractory HNSCC. This is the first report of “real-world” data on promising antitumor efficacy of SG in a heavily pretreated oral cancer patient with Trop-2 overexpression. Consistent with the findings of the Basket TROPiCS-03 study, SG appears to be a promising novel therapy option for R/M HNSCC after failure of immunotherapy and chemotherapy, particularly in patients with Trop-2 overexpression. Full article

The incidence of human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) has increased substantially over the past three decades, and since 2017, it has been recognized in the AJCC staging system as distinct from its HPV-negative counterpart. The underlying mechanisms of HPV-associated carcinogenesis, tumor microenvironment, and host immune response represent opportunities for therapeutic development. While anti-PD-1 immunotherapy is now part of standard treatment for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) in general, there are no established immunotherapeutic strategies specifically for HPV-related HNSCC. In this context, multiple emerging approaches are being actively studied—among these are therapeutic vaccines with or without anti-PD-(L)1 adjuvants, peptide–HLA-based immunotherapeutic platforms, and adoptive cell therapies including tumor-infiltrating lymphocytes (TILs), T-cell receptor (TCR) therapy, and chimeric antigen receptor (CAR) T-cell therapy. Beyond further maturation of these novel immunotherapeutic strategies, additional work is needed to delineate the optimal disease state of application (localized versus recurrent/metastatic), as well as in the development of small molecule inhibitors targeting HPV-specific mechanisms of viral oncogenesis. Full article

Disease progression and treatment resistance in colorectal and other cancers are driven by a subset of cells within the tumor that have stem-cell-like properties and long-term tumorigenic potential. These stem-cell-like cells express the leucine-rich G repeat-containing protein-coupled receptor 5 (LGR5) and have characteristics similar to tissue-resident stem cells in normal adult tissues such as the colon. Organoid models of murine and human colorectal and other cancers contain LGR5-expressing (LGR5+) stem-cell-like cells and can be used to investigate the underlying mechanisms of cancer development, progression, therapy vulnerability, and resistance. A large biobank of organoids derived from colorectal cancer or adjacent normal tissue was developed. We performed a large-scale unbiased functional screen to identify bispecific antibodies (BsAbs) that preferentially inhibit the growth of colon tumor-derived, as compared to normal tissue-derived, organoids. We identified the most potent BsAb in the screen as petosemtamab, a Biclonics^® BsAb targeting both LGR5 and the epidermal growth factor receptor (EGFR). Petosemtamab employs three distinct mechanisms of action: EGFR ligand blocking, EGFR receptor internalization and degradation in LGR5+ cells, and Fc-mediated activation of the innate immune system by antibody-dependent cellular phagocytosis (ADCP) and enhanced antibody-dependent cellular cytotoxicity (ADCC) (see graphical abstract). Petosemtamab has demonstrated substantial clinical activity in recurrent/metastatic head and neck squamous cell carcinoma (r/m HNSCC). The safety profile is generally favorable, with low rates of skin and gastrointestinal toxicity. Phase 3 trials are ongoing in both first-line programmed death-ligand 1-positive (PD-L1+) and second/third-line r/m HNSCC. Full article

Cutaneous squamous cell carcinoma (cSCC) is a common cancer with increasing incidence and 5% of patients develop incurable disease, often resistant to chemotherapy. The anti-PD-1 therapy cemiplimab has shown high efficacy in clinical trials. This retrospective study evaluated the real-world effectiveness of cemiplimab in incurable cSCC and examined factors influencing response and toxicity. Data from 86 patients across three UK healthcare providers were analysed. Median progression-free survival (PFS) and overall survival (OS) were not reached, with 38% showing durable responses beyond 12 months. The overall response rate was 60.8% (95% CI 49–71), and the clinical benefit rate was 74.3% (95% CI 63–83). A head and neck primary site was associated with improved PFS (p = 0.008) and OS (p = 0.023), while concurrent immunosuppression was associated with worse PFS (p < 0.001). These findings align with clinical trials, suggesting cemiplimab is effective and safe in the recurrent/metastatic setting. Full article

Accumulation of evidence highlighted the crosstalk between DNA damage repair and the immune system. Herein, we tested the hypothesis that in head and neck squamous cell carcinoma (HNSCC), the DNA repair capacity of patients’ PBMCs correlates with therapeutic response to immune checkpoint blockade. Following in vitro UVC irradiation, oxidative stress, apurinic/apyrimidinic (AP) lesions, endogenous/baseline DNA damage, and DNA damage repair efficiency were evaluated in three HNSCC (UM-SCC-11A, Cal-33, BB49) and two normal cell lines (RPMI-1788, 1BR-3h-T), as well as in peripheral blood mononuclear cells (PBMCs) from 15 healthy controls (HC) and 49 recurrent/metastatic HNSCC patients at baseline (8 responders, 41 non-responders to subsequent nivolumab therapy). HNSCC cell lines showed lower DNA repair efficiency, increased oxidative stress, and higher AP sites than normal ones (all p < 0.001). Moreover, patients’ PBMCs exhibited increased endogenous/baseline DNA damage, decreased DNA repair capacity, augmented oxidative stress, and higher AP sites than PBMCs from HC (all p < 0.001). Importantly, PBMCs from responders to nivolumab therapy showed lower endogenous/baseline DNA damage, higher DNA repair capacities, decreased oxidative stress, and reduced AP sites than non-responders (all p < 0.05). Together, we demonstrated that oxidative stress status and DNA repair efficiency in PBMCs from HNSCC patients are correlated with the response to immune checkpoint blockade. Full article

Objectives: The primary aim of this phase 1 trial is to establish the recommended phase 2 dose (RP2D) of tazemetostat given with a fixed dose of pembrolizumab in patients with recurrent or metastatic head and neck squamous cell carcinomas (RM-HNSCCs). Methods: A 3 + 3 dose-escalation phase 1 design was used to assess three dose-levels of tazemetostat (400, 600, and 800 mg orally, twice daily) with pembrolizumab (200 mg intravenously). Cycle 1 was 35 days (tazemetostat days 1–35; pembrolizumab day 15). Subsequent cycles were 21 days (tazemetostat days 1–21; pembrolizumab day 1). Dose-limiting toxicity (DLT), assessed during cycle 1, was defined as study-drug-related grade 4 neutropenia or thrombocytopenia, grade 3 febrile neutropenia, or grade 3–4 non-hematologic adverse events (AEs). Patients had to have completed cycle 1 to be evaluable for the DLT assessment; otherwise, an equal number of additional patients were enrolled. The RP2D was defined as the highest dose level in which zero of three or less than or equal to one of six patients experienced a DLT. Results: Twelve patients were enrolled: three on 400 mg, three on 600 mg, and six on the 800 mg dose level of tazemetostat. Three patients on the 800 mg dose level did not complete cycle 1 and were not evaluable for DLT. In the other nine patients, DLTs did not occur during cycle 1. In all 12 patients, the most common AEs included anemia (10 patients), fatigue (eight), and hyponatremia (seven). Conclusions: Among the patients with RM-HNSCCs, the RP2D of tazemetostat was 800 mg and administered twice daily when given with pembrolizumab. Full article

Background: Head and neck cancer is a deadly disease with over 500,000 cases annually worldwide. Metastatic head and neck cancer accounts for a large proportion of the mortality associated with this disease. Many advances have been made in our understanding of the mechanisms of metastasis. The application of immunotherapy to locally recurrent or metastatic head and neck cancer has not only improved oncologic outcomes but has also provided valuable insights into the mechanisms of immune evasion and ultimately treatment failure. Objectives: This review paper will review our current understanding of biological mechanisms of treatment failure and metastasis. Published and ongoing clinical trials in the management of metastatic head and neck cancer will also be summarized. Methods: A narrative review was conducted to address the current understanding of the mechanisms of treatment failure and current treatment paradigms in recurrent and metastatic head and neck carcinoma. Conclusions: Our understanding of treatment failure in this disease is rapidly evolving. Immunotherapy represents a valuable new tool in the fight against recurrent and metastatic head and neck squamous cell carcinoma. Integrating patient and tumor specific data via artificial intelligence and deep learning will allow for a precision oncology approach, thereby achieving better prognostication and management of patients with this deadly disease. Full article

Immune checkpoint inhibitors (ICIs) are effective in treating recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), but only 20% of patients achieve durable responses. This study evaluated circulating tumor DNA (ctDNA) as a real-time biomarker for monitoring treatment response in HNSCC. The SHIZUKU-HN study prospectively collected and analyzed serial plasma samples (n = 27) from HNSCC patients undergoing ICIs, using Guardant360 to assess ctDNA variant allele frequency (VAF) and genetic mutations. Tumor volumes were quantified using 3D reconstruction of CT scans, and data from Japan’s C-CAT database (n = 2255) provided insights into ctDNA testing in HNSCC. C-CAT data showed that ctDNA testing was underutilized, performed in only 7% of head and neck cancer cases. In SHIZUKU-HN, mean VAF significantly correlated with tumor volume (Spearman’s ρ = 0.70, p = 0.001), often preceding radiographic progression. BRAF and APC mutations disappeared in partial responders, while GNAS mutations varied. EGFR and PIK3CA amplifications, detectable via ctDNA but missed in tissue biopsies, indicated emerging resistance mechanisms. The SHIZUKU-HN study demonstrates the potential of ctDNA as a dynamic biomarker in HNSCC, offering early insights into treatment efficacy and informing personalized ICI therapy. Full article

Head and neck squamous cell carcinomas (HNSCC) have an overall poor prognosis, especially in locally advanced and metastatic stages. In most cases, multimodal therapeutic approaches are required and show only limited cure rates with a high risk of tumor recurrence. Anti-PD-1 antibody treatment was recently approved for recurrent and metastatic cases but to date, response rates remain lower than 25%. Therefore, the investigation of the immunological tumor microenvironment and the identification of novel immunotherapeutic targets in HNSCC is of paramount importance. In our study, we used tissue samples of n = 116 HNSCC patients for the immunohistochemical detection of the intratumoral and peritumoral expression of T cell exhaustion markers (PD-1, LAG-3, TIM-3) on tumor infiltration leukocytes (TIL), as well as the expression level of stromal senescence markers (IL-8, MMP-3) on tumor-associated fibroblasts. The clinical parameter of the vitamin D serum status as well as the histopathological HPV infection status of the tumor was correlated with the expression rates of the biomarkers and the overall patient survival. An increased peritumoral and intratumoral expression of the biomarkers PD-1 and TIM-3 significantly correlated with improved overall patient survival. A high peritumoral expression of LAG-3 correlated with better overall survival. A positive HPV tumor status correlated with a significantly elevated expression of PD-1 and TIM-3. Biomarkers of stromal senescence showed no influence on the patient outcome. However, the vitamin D serum status showed no influence on patient outcomes or biomarker expressions. Our study identified PD-1, LAG-3, and TIM-3 as promising targets of a therapeutic strategy targeting the tumor microenvironment in HNSCC, particularly among HPV-positive patients, where a higher expression of these checkpoints correlated with an improved overall survival. These findings support the potential of antibodies targeting these immune checkpoints to enhance treatment efficacy, especially in the context of bispecific targeting. Full article

Radiotherapy (RT) is an integral component in the multidisciplinary management of patients with head and neck squamous cell carcinoma (HNSCC). Significant advances have been made toward optimizing tumor control and toxicity profiles of RT for HNSCC in the past two decades. The development of intensity modulated radiotherapy (IMRT) and concurrent chemotherapy established the standard of care for most patients with locally advanced HNSCC around the turn of the century. More recently, selective dose escalation to the most radioresistant part of tumor and avoidance of the most critical substructures of organs at risk, often guided by functional imaging, allowed even further improvement in the therapeutic ratio of IMRT. Other highly conformal RT modalities, including intensity modulated proton therapy (IMPT) and stereotactic body radiotherapy (SBRT) are being increasingly utilized, although there are gaps in our understanding of the normal tissue complication probabilities and their relative biological effectiveness. There is renewed interest in spatially fractionated radiotherapy (SFRT), such as GRID and LATTICE radiotherapy, in both palliative and definitive settings. The emergence of immune checkpoint inhibitors (ICIs) has revolutionized the treatment of patients with recurrent and metastatic HNSCC. Novel RT modalities, including IMPT, SBRT, and SFRT, have the potential to reduce lymphopenia and immune suppression, stimulate anti-tumor immunity, and synergize with ICIs. The next frontier in the treatment of HNSCC may lie in the exploration of combined modality treatment with new RT technologies and ICIs. Full article

Background: Previously, we proposed that the immune-modified Glasgow Prognostic Score (imGPS), which adds the lymphocyte count to the mGPS, is helpful as a prognostic marker for patients with head and neck squamous cell carcinoma. In this study, we investigated the imGPS as a marker for the therapeutic effect of pembrolizumab in treating recurrent and metastatic head and neck cancer (RMHNC). Methods: This study included RMHNC patients who were treated with pembrolizumab from December 2019 to April 2024. ALB, CRP, lymphocyte counts, neutrophil-to-lymphocyte ratios (NLRs), mGPSs, and imGPSs were extracted as biomarkers, and the response rate and prognosis were analyzed for each. Results: A total of 54 patients were enrolled. Lymphocyte counts were correlated with the overall response rates (ORRs) (p = 0.0082). Although the mGPS did not show significant differences in ORRs, imGPSs revealed a significant difference (p = 0.013). CRP, ALB, and lymphocyte counts were correlated with overall survival (OS) and/or progression-free survival (PFS). NLRs, mGPSs, and imGPSs were also correlated with OS and/or PFS, with imGPSs showing the greatest area under the curve (OS; AUC = 0.795, PFS; AUC = 0.754). Conclusions: This study demonstrates that the imGPS is an excellent predictive marker for the therapeutic effect and prognosis of pembrolizumab for RMHNC. The imGPS can be employed with daily blood tests, highlighting the potential to forecast the impact of the ICI with high reliability. Full article

Squamous cell carcinoma of the head and neck (SCCHN) is among the ten most common cancers worldwide, with advanced SCCHN presenting with a 5-year survival of 34% in the case of nodal involvement and 8% in the case of metastatic disease. Disease-free survival at 2 years is 67% for stage II and 33% for stage III tumors, whereas 12–30% of patients undergo distant failures after curative treatment. Previous treatments often hinder the success of salvage surgery and/or reirradiation, while the standard of care for the majority of metastatic SCCHN remains palliative chemo- and immuno-therapy, with few patients eligible for locoregional treatments. The aim of this paper is to review the characteristics of recurrent SCCHN, based on different recurrence sites, and metastatic disease; we will also explore the possibilities not only of salvage surgery and reirradiation but also systemic therapy choices and locoregional treatment for metastatic SCCHN. Full article

Head and neck squamous cell carcinoma (HNSCC) is the sixth leading cause of cancer worldwide according to GLOBOCAN estimates from 2022. Current therapy options for recurrent or metastatic disease are limited to conventional cytotoxic chemotherapy and immunotherapy, with few targeted therapy options readily available. Recent single-cell transcriptomic analyses identified TGF-β signaling as an important mediator of functional interplays between cancer-associated fibroblasts and a subset of mesenchymal cancer cells. This signaling was shown to drive invasiveness, treatment resistance, and immune evasion. These data provide renewed interest in the TGF-β pathway as an alternative therapeutic target, prompting a critical review of previous clinical data which suggest a lack of benefit from TGF-β inhibitors. While preclinical data have demonstrated the great anti-tumorigenic potential of TGF-β inhibitors, the underwhelming results of ongoing and completed clinical trials highlight the difficulty actualizing these benefits into clinical practice. This topical review will discuss the relevant preclinical and clinical findings for TGF-β inhibitors in HNSCC and will explore the potential role of patient stratification in the development of this therapeutic strategy. Full article