cell therapies

2025-10-29 | Dental implant-associated oral squamous cell carcinoma: a clinical retrospective study of 22 cases

BACKGROUND: In oral cavity, oral squamous cell carcinoma (OSCC) is the most common malignant neoplasm. Established risk factors for OSCC include tobacco use, genetic predisposition, viral infections, and poor oral hygiene. With the increasing prevalence of dental implant (DI) procedures, reports of OSCC developing around implants have also risen. This study aims to investigate potential risk factors and clinical characteristics of OSCC occurring in association with dental implants, in order to improve understanding of its etiology and prognosis. METHODS: This retrospective study analyzed the medical records of 22 patients diagnosed with OSCC around dental implants at the Department of Oral and Maxillofacial Surgery at a single institution, between 2009 and 2024 by a single surgeon. All patients presented with persistent discomfort or abnormal lesions following implant placement and were subsequently diagnosed with OSCC via histopathological examination. Pre-treatment imaging included magnetic resonance imaging, contrast-enhanced computed tomography, PET/CT, and bone scans. The 8th edition of the American Joint Committee on Cancer (AJCC) guidelines was used to determine cancer staging. Data were collected on patient demographics, smoking and alcohol histories, implant placement date, and histopathologic findings through electronic medical records. RESULT: All 22 patients presented with inflammatory lesions or progressive bone loss around dental implants. Five patients had a history of malignancy in other organs or hematologic disease. Six male patients had habitual alcohol consumption and smoking. OSCC occurred predominantly in the mandible (77.3%), with 95.5% of tumors classified as T4 at diagnosis. Neck metastasis developed in 41% of patients (9/22), including four cases of delayed/occult nodal involvement. The mean interval from implant placement to OSCC diagnosis was 4.7 years, with nearly half diagnosed within 1 year. Histopathology revealed only well- or moderately differentiated tumors, with bone invasion present in 95.5% of cases. The mean depth of invasion was 13.2 mm. Twenty patients underwent surgical resection, while two received nonsurgical treatment due to systemic condition. The mean survival time was 25.7 months, and Kaplan-Meier analysis showed no significant survival difference between maxillary and mandibular OSCC. CONCLUSION: OSCC after dental implant placement, though uncommon, is a significant clinical issue due to its late diagnosis, aggressive bone invasion, and poor prognosis. Our findings underscore the importance of differentiating OSCC from peri-implantitis and recommend prompt biopsy when peri-implant inflammation persists despite conventional treatment. Early recognition may improve survival outcomes. The observed links with prior malignancy, chronic inflammation, and lifestyle risk factors suggest a multifactorial etiology, highlighting the need for further longitudinal studies to refine prevention and early detection strategies.

Open article ↗

2025-10-01 | Outer Membrane Vesicles Derived from Oral Bacteria Act as a Dagger in Host Immunity: Insight Tips from Local Diseases to Systemic Effects

and other important periodontal pathogens can destroy the host structure, induce host immune responses, and promote periodontitis progression. In oral squamous cell carcinoma (OSCC), OMVs accelerate cancer spread and metastasis by regulating the gene expression of tumour cells. In addition to their role in oral diseases, OMVs can spread from the oral cavity to the whole body, thereby participating in the development of many diseases, including circulatory diseases, endocrine diseases, autoimmune diseases, and neurologic diseases. In this review, we introduce the biogenesis, basic structure, and roles of OMVs and comprehensively summarize the biological characteristics of OMVs from various oral bacteria. In addition, we describe the impact of OMVs on oral diseases as well as systemic health and emphasize their therapeutic potential as drug targets, antigens, and immune adjuvants for application in periodontitis and OSCC. Finally, we discuss in depth the future research directions, application prospects, and challenges of OMVs.

Open article ↗

2025-09-24 | Tumor-Infiltrating Lymphocytes Predict Extranodal Extension and Prognosis in Regionally Advanced Oral Cavity Cancer

Background/Objectives: Oral cavity squamous cell carcinoma (OCSCC) is an aggressive malignancy, often diagnosed at an advanced stage and with stagnant survival outcomes despite advances in surgical and oncologic management. Tumor-infiltrating lymphocytes (TILs) have been explored as potential prognostic markers in many solid tumors; however, their role in OCSCC remains under researched. This study aimed to assess the prognostic value of TILs in a cohort of patients with regionally advanced, p16-negative squamous cell carcinoma of all oral cavity subsites and to evaluate for any correlation of TILs and extranodal extension (ENE). Methods: A retrospective study was conducted on 103 consecutive patients treated with comprehensive surgical resection. TILs were quantified using the standardized method proposed by the International Immuno-Oncology Biomarkers Working Group. Statistical analyses evaluated associations with a comprehensive set of independent variables and survival endpoints. Results: High stromal infiltration at the invasive margin (>25%) was independently associated with significantly improved overall survival (HR 4.53, p = 0.005), disease-specific survival (HR 4.49, p = 0.008), and disease-free survival (HR 3.42, p = 0.025). Patients with ENE demonstrated lower TILs compared with ENE-negative patients (median 40% vs. 57.5%), a difference that reached statistical significance in both parametric and nonparametric testing (Welch’s t-test p = 0.032; Mann–Whitney U p = 0.030). Conclusions: TILs quantified by this standardized method are a reliable, independent prognostic biomarker in regionally advanced OCSCC of all subsites and are also associated with extranodal extension of regional metases. This study gives rationale for consideration of inclusion of TILS into future immunotherapeutic decision-making and further investigations of TIL-ENE association.

Open article ↗

2025-09-02 | Cancer stem cell mechanisms and targeted therapeutic strategies in head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma (HNSCC) originates in the epithelial lining of the oral cavity, pharynx, and larynx, with over 830,000 new cases diagnosed globally in 2020, making it the seventh most prevalent cancer. Despite treatment advances, high-grade HNSCCs remain associated with poor outcomes and a high risk of recurrence. Although Cancer Stem Cells (CSCs) are rare in HNSCC tumors, they are key drivers of tumor relapses, as they evade apoptosis and survive current therapies through enhanced DNA repair and quiescence. This review integrates recent discoveries into a unified framework for understanding CSC mechanisms. It examines the role of pluripotency factors, biomarkers, replicative immortalization, metabolic reprogramming, redox regulation, and immune evasion in shaping CSC behavior and survival under treatment stress. Non-coding RNAs are also discussed as modulators of gene expression via epigenetic regulation in CSCs. Importantly, it highlights how these adaptive mechanisms intersect as potential vulnerabilities that could be exploited to eliminate CSCs through targeting multiple pathways. Finally, it provides recent and emerging precision therapeutics, including CAR-T cells, immune checkpoint inhibitors, metabolic and redox-targeting agents, and epigenetic modulators currently in preclinical and clinical trials applications designed to eliminate CSCs and improve patient outcomes in HNSCC.

Open article ↗

2025-06-20 | Reliability of Pectoralis Major Myocutaneous Flap Reconstruction in Patients with Oral Cavity Squamous Cell Carcinoma in the Era of Free Flap Reconstruction: Our Experience and Review of Literature

ABSTRACT Background: The incidence of oral cavity cancers is rising globally. Surgical excision forms the mainstay of treatment of these lesions. The locally advanced stage of presentation makes the excision and reconstruction extremely challenging. The current gold standard for reconstruction is microvascular free flap reconstruction. Pectoralis major myocutaneous (PMMC) flap still remains a viable option due to its anatomical advantages including ease of harvest and lower technical demands. This study highlights the technique, reliability, and outcomes of PMMC flap reconstruction. Materials and Methods: A retrospective study was done including 70 patients with oral squamous cell carcinoma who underwent surgical resection (wide local excision and neck dissection) followed by reconstruction using PMMC flap through submammary approach. Results: The majority of patients were males (47), with a mean age of 48 years. The most common site of carcinoma was buccal mucosa (41). Intraoral wound dehiscence of the flap occurred in 10% of cases healing naturally. Complete necrosis was seen in 3 cases (4.28%) of which only one case required salvage flap reconstruction. Minor complications included axillary seroma which was seen in 5.7% of patients. Conclusion: PMMC flap continues to be a viable option for reconstruction in oral cancers even in the era of free flap repair. It can be still reliably be used as a method of reconstruction particularly in developing countries like India, where financial limitations and a lack of specialized medical infrastructure make more complex techniques less feasible.

Open article ↗

small molecules

2026-07-18 | Ferroptosis Biomarkers in HPV-Negative Head and Neck Squamous Cell Carcinoma

Background/Objectives: Head and neck squamous cell carcinoma (HNSCC) is an aggressive cancer of the oral cavity, pharynx, larynx and upper airway. HNSCC is subdivided into distinct clinical entities based on the presence or absence of high-risk human papillomavirus (HPV) infection. While HPV-positive HNSCC patients respond better to conventional and targeted therapies than HPV-negative cases, recurrence is more frequent in HPV-negative cases with limited treatment options. Ferroptosis is a form of iron-based programmed cell death caused by excessive lipid peroxide accumulation. Biomarkers of ferroptosis have proven useful for identifying and triggering ferroptosis in models of treatment-resistant cancers. Identifying and understanding ferroptosis biomarker function in HPV-negative HNSCC allows the possibility for more effective treatment strategies. Methods: Literature searches combined with the public online ferroptosis database FerrDB V3 were utilized for the objective identification and classification of established and non-established ferroptosis biomarkers in HPV-negative HNSCC. Additional novel biomarkers were identified based on known roles in HNSCC oncogenesis. Results: A total of 30 ferroptosis biomarkers were identified associated with HPV-negative disease. Biomarkers were grouped according to shared biological functions, with each marker summarized for prognostic and mechanistic roles in HNSCC ferroptosis. Conclusions: The described biomarkers present a means for stratifying tumors for ferroptotic induction, with several offering potential novel methods for overcoming refractory HPV-negative disease. These biomarkers may warrant further investigation into devising future patient-tolerant strategies that selectively activate ferroptosis in HPV-negative HNSCC.

Open article ↗

2026-06-17 | Aspirin initiation and dose-dependent risk reduction of oral squamous cell carcinoma in areca nut chewers

BACKGROUND: Oral cavity squamous cell carcinoma (OCSCC) driven by areca nut consumption-a Group 1 carcinogen affecting 600 million people globally-represents a significant unmet need in precision prevention. Despite the known role of COX-2-mediated inflammation in this etiologic niche, pharmacological strategies remain under-evaluated. METHODS: We emulated a target trial using a nationwide matched cohort of 50,606 areca nut chewers from the Taiwan National Health Insurance Research Database (2008 to 2021). To minimize selection and immortal time biases, we utilized time-dependent exposure modeling and Fine-Gray subdistribution hazard models to account for competing mortality. RESULTS: Aspirin initiation was associated with a significantly lower risk of incident OCSCC (adjusted sHR, 0.75; 95% CI, 0.65-0.87; P<.001). We identified a robust dose-response relationship, with a 43% risk reduction observed in the high-cumulative-exposure group (≥ median cDDD; sHR, 0.57; 95% CI, 0.47-0.69). The exploratory estimated 5-year number needed to treat (NNT) was 249 for the high-dose group. Sensitivity analyses, including E-value assessment (2.89) and landmark tracking, confirmed the stability of this association against unmeasured confounding and reverse causality. CONCLUSIONS: Our findings provide large-scale human evidence that sustained aspirin use significantly alters the trajectory of oral field cancerization in areca nut chewers. This study identifies aspirin as a high-priority candidate for risk-stratified chemoprevention in global populations with high areca nut exposure.

Open article ↗

2026-06-03 | Ultra-low-dose immunotherapy plus oral metronomic chemotherapy versus paclitaxel-carboplatin in platinum-sensitive recurrent or metastatic head and neck squamous cell carcinoma: A randomized phase III trial.

LBA6007 Background: Standard first-line therapy for recurrent or metastatic head and neck squamous cell carcinoma (R/M-HNSCC) includes platinum-based chemotherapy (PBC) combined with pembrolizumab or cetuximab; however, these regimens remain inaccessible for many patients globally, particularly in resource-limited settings. Triple oral metronomic chemotherapy combined with ultra-low-dose immunotherapy (TMC-I) has demonstrated promising activity and tolerability in earlier studies. We conducted a randomized phase III trial comparing TMC-I with PBC (paclitaxel and carboplatin) in patients with R/M-HNSCC receiving first-line palliative therapy. Methods: In this open-label, multicenter, phase III trial conducted at two centers, 422 patients with R/M-HNSCC were randomized (1:1) to receive paclitaxel 175 mg/m² plus carboplatin AUC 6 every 3 weeks (Arm-A) or TMC-I (oral methotrexate 9 mg/m² weekly, celecoxib 200 mg twice daily, erlotinib 150 mg daily, and nivolumab 20 mg IV every 3 weeks) (Arm-B). Treatment continued until disease progression or unacceptable toxicity. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), safety, and quality of life (QoL). The planned sample size of 422 patients (211 per arm) provided 80% power with a two-sided α of 0.05. The trial was registered with the Clinical Trials Registry–India (CTRI/2024/01/061661). Results: The median age was 49.5 years (IQR 42–58), 85.5% were male, 78.9% had oral tobacco use, 76.3% had oral cavity primaries, 25.6% had metastatic disease, and 30.6% had ECOG performance status 2. After a median follow-up of 10.8 months (95% CI 8.1–13.6) in Arm-A and 11.9 months (95% CI 10.3–13.4) in Arm-B, the primary endpoint of OS was significantly improved with TMC-I compared with PBC. Twelve-month OS was 46% versus 23%, and six-month OS was 69% versus 52% (p < 0.001). Median OS was 10.3 versus 6.2 months (HR 0.565, 95% CI 0.439–0.728; p < 0.001). Median PFS was 5.5 versus 2.7 months (HR 0.465, 95% CI 0.371–0.582; p < 0.001). ORR was higher with TMC-I than with PBC (53.4% vs 24.1%; p < 0.001), with fewer grade ≥3 adverse events (34.1% vs 46.4%; p = 0.010). No treatment-related deaths were observed, and patient-reported QoL was preserved with TMC-I. Conclusion: TMC-I significantly improved survival outcomes and response rates while reducing severe toxicity and preserving QoL compared with PBC. At approximately USD 230 per month, TMC-I represents a promising and cost-effective first-line treatment option for patients with R/M-HNSCC. Clinical trial information: CTRI/2024/01/061661.

Open article ↗

2026-05-27 | Metronomic adjuvant chemotherapy (MACE) in locally advanced oral cavity squamous cell carcinoma post-surgery and adjuvant treatment (MACE postop): A phase III randomized controlled trial.

6002 Background: The role of maintenance systemic therapy following definitive surgery and adjuvant treatment in locally advanced oral cavity squamous cell carcinoma (OCSCC) remains undefined. This phase III trial evaluated whether oral metronomic adjuvant chemotherapy (MACE) improves survival compared with observation. Methods: This multicenter, open-label, phase III superiority trial conducted in India enrolled patients with stage II–IV OCSCC (AJCC 7th edition) who were clinico-radiologically disease-free 1–2 months after completion of definitive surgery with adjuvant treatment. Patients were randomly assigned (1:1) to observation (OBS) or oral MACE for up to 18 cycles. MACE comprised methotrexate 15 mg/m² once weekly (four doses per 28-day cycle) plus celecoxib 200 mg twice daily. Adherence to MACE was monitored at 3-monthly follow-up visits using patient-reported medication logs, supplemented by objective verification through review of returned empty drug containers. The primary endpoint was 2-year overall survival (OS). The planned sample size was 712; accrual was stopped early following emerging external evidence, with ethics committee approval. Results: Between February 2017 and April 2025, 410 patients were enrolled (OBS, n=208; MACE, n=202); approximately three-quarters had stage IV disease in both arms. The median number of MACE cycles delivered was 15; 92 patients discontinued treatment, most commonly because of noncompliance (n=55) or disease progression (n=27). At a median follow-up of 42.5 months, 129 deaths were observed (70 in OBS and 59 in MACE). Two-year OS was 70.2% (95% CI, 63.0–76.2) in the OBS arm and 79.2% (95% CI, 72.5–84.4) in the MACE arm (hazard ratio [HR], 0.76; p=0.13). Two-year progression-free survival was 68.0% (95% CI, 61.0–74.1) with OBS and 77.0% (95% CI, 70.2–82.4) with MACE (HR, 0.72; p=0.044). Distant recurrences occurred in 30 patients (14.4%) in the OBS arm and 17 patients (8.4%) in the MACE arm, while second primary malignancies were observed in 8 (3.8%) and 3 (1.5%) patients, respectively. Grade 3–4 toxicity with MACE was observed in 6.9%. Exploratory subgroup analyses suggested greater benefit in patients with extranodal extension and stage IV disease. The average cost of MACE per cycle, including toxicity management, was approximately USD 10. Conclusions: MACE following definitive local therapy did not significantly improve overall survival in locally advanced OCSCC. However, a statistically significant improvement in progression-free survival was observed, driven by a reduction in distant metastases and second primary malignancies. These findings suggest that selected high-risk subgroups—particularly patients with extranodal extension and advanced-stage disease—may derive benefit from this low-cost and well-tolerated strategy. Clinical trial information: CTRI/2017/02/007777.

Open article ↗

2026-04-15 | Nutritional prehabilitation in head and neck cancer patients (PreHead) - A randomized controlled trial study protocol.

Up to 60% of patients with head and neck cancer are malnourished upon first presentation. Malnutrition has been associated with a higher risk of adverse events and decreased quality of life and survival. Patients with a high risk of malnutrition often receive pretreatment dietary treatment before surgery or (chemo)radiotherapy, i.e., nutritional prehabilitation. However, previous research suggests that patients with a low or medium risk of malnutrition may also benefit from nutritional prehabilitation. To investigate the effect of nutritional prehabilitation on adverse events, nutritional status, patient-reported quality of life, tumor recurrence, and (disease-specific and overall) survival. To evaluate the cost-effectiveness of nutritional prehabilitation compared with standard care. A single-center, non-blinded, randomized controlled trial. Patients with locoregionally advanced stage (III or IV) primary mucosal squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx or larynx treated with curative intent and with a low or medium risk of malnutrition according to the Malnutrition Universal Screening tool. Based on a power analysis, a total of 128 patients will be included. The intervention arm will receive nutritional prehabilitation and the control arm will receive standard care (no nutritional prehabilitation). Adverse events (i.e., surgical complications and (chemo)radiotherapy toxicity). Complications will be measured within 30 days after surgery using the Clavien-Dindo classification. Toxicity will be evaluated using the Common Terminology Criteria for Adverse Events (CTCAE), 6 and 12 weeks after the start of (chemo)radiotherapy. It is hypothesized that nutritional prehabilitation, compared with no nutritional prehabilitation, will result in fewer (severe) adverse events, improvement of nutritional status, higher quality of life, equal risk of recurrence and better survival. It is hypothesized that the intervention will be cost-effective. The trial is registered in the Dutch Trial Register under registration number NL87676.042.24.

Open article ↗

proteins

2025-06-27 | Evaluation of the Antitumor and Antiproliferative Potential of Synthetic Peptides Derived from IsCT1, Associated with Cisplatin, in Squamous Cell Carcinoma of the Oral Cavity.

Head and neck squamous cell carcinoma (SCC), particularly in the oral cavity, is among the most prevalent and lethal forms of cancer globally. Current therapeutic strategies, predominantly involving cisplatin, face challenges like chemoresistance and toxicity to normal cells, justifying the exploration of new approaches. This study evaluates the antitumor, antiproliferative, and immunomodulatory potential of a synthetic peptide derived from IsCT1 (Isalo scorpion cytotoxic peptide), named AC-AFPK-IsCT1, in combination with cisplatin in oral squamous cell carcinoma cellular models. Tumor and normal cells were treated with varying concentrations of cisplatin and peptide, and the cytotoxicity was measured through an MTT assay, while apoptosis and cell cycle alterations were assessed via flow cytometry. Interestingly, the combination of AC-AFPK-IsCT1 with cisplatin exhibited higher specificity for tumor cells, significantly reducing IC50 values compared to cisplatin used as a single agent. Moreover, the combination treatment induced pronounced S-phase cell cycle arrest and enhanced apoptotic activity, evidenced by the upregulation of caspase-3, caspase-8, and p53, while maintaining low toxicity in normal fibroblast cells. The peptide also modulated the mitochondrial membrane potential, further contributing to the activation of intrinsic apoptotic pathways. The data suggest that AC-AFPK-IsCT1 potentiates the antitumor effects of cisplatin by engaging both intrinsic and extrinsic apoptotic pathways while preserving normal cell viability. These findings underscore the potential of combining cisplatin with AC-AFPK-IsCT1 as a promising therapeutic strategy for improving the efficacy of chemotherapy in SCC, reducing systemic toxicity, and overcoming chemoresistance.

Open article ↗

2025-03-21 | Neoadjuvant leukocyte interleukin injection immunotherapy improves overall survival in low-risk locally advanced head and neck squamous cell carcinoma –the IT-MATTERS study

The randomized controlled pivotal phase 3 study evaluated efficacy and safety of neoadjuvant complex biologic, Leukocyte Interleukin Injection (LI), administered for 3 consecutive weeks pre-surgery, in treatment naïve resectable locally advanced primary squamous cell carcinoma of oral cavity and soft palate. Randomization 3:1:3 to LI+/-CIZ (cyclophosphamide, indomethacin, and zinc)+SOC, or SOC (standard of care) alone. LI-treated patients received 400 IU (as interleukin-2 equivalent; 200 IU peritumorally, 200 IU perilymphatically) sequentially, daily 5 days/week for 3 weeks before surgery. All subjects were to receive SOC. Post-surgery, patients with low risk for recurrence were to receive radiotherapy, while those with high risk received concurrent chemoradiotherapy. Median follow-up was 56 months. There were 923 ITT (Intent-to-Treat) subjects (380 ITT low-risk and 467 ITT high-risk). Pre-surgery objective early response (45 objective early responders; 5 complete responses [CRs], 40 partial responses [PRs], confirmed by pathology at surgery. LI (+/- CIZ) had 8.5% objective early responders (45/529 ITT) and 16% objective early responders (34/212 ITT low-risk) vs. no reported SOC objective early responders (0/394 ITT). Objective early responders significantly lowered death rate to 22.2% (ITT LI-treated), 12.5% (ITT low-risk LI + CIZ + SOC), while the ITT low-risk SOC death rate was 48.7%. Thus, objective early response impacted overall survival (OS); proportional hazard ratios were 0.348 (95% CI: 0.152-0.801) for ITT low-risk LI-treated, 0.246 (95% CI: 0.077-0.787) for ITT low-risk LI + CIZ + SOC. ITT low-risk LI + CIZ + SOC demonstrated significant OS advantage vs. ITT low-risk SOC (unstratified log-rank p = 0.048; Cox hazard ratio = 0.68; 95% CI: 0.48-0.95, Wald p = 0.024 [controlling for tumor stage, tumor location, and geographic region]). Absolute OS advantage increased over time for ITT low-risk (LI + CIZ + SOC)-treated vs. ITT low-risk SOC: reaching 14.1% (62.7% vs. 48.6%) at 60 months, with 46.5 months median OS advantage (101.7 months vs. 55.2 months), respectively. Quality of life benefit for complete responders sustained for >3 years post LI treatment. Percent treatment-emergent adverse events were comparable among all treated groups. No excess safety issues were reported for LI over SOC alone post-surgery. NCT01265849, EUDRA:2010-019952-35.

Open article ↗

2025-02-05 | Mistletoe Lectin Induces Apoptosis and Modulates the Cell Cycle in YD38 Oral Squamous Cell Carcinoma Cells

Objectives: Despite progress in therapeutic interventions, squamous cell carcinoma of the oral cavity (OSCC) continues to pose a substantial burden on public health, with persistently poor patient outcomes. This investigatio... | Find, read and cite all the research you need on Tech Science Press

Open article ↗

2024-09-24 | Antitumoral and Antiproliferative Potential of Synthetic Derivatives of Scorpion Peptide IsCT1 in an Oral Cavity Squamous Carcinoma Model

The oral cavity is a frequent site for head and neck cancers, which rank as the sixth most common cancer globally, with a 5-year survival rate slightly over 50%. Current treatments are limited, and resistance to therapy remains a significant clinical obstacle. IsCT1, a membrane-active peptide derived from the venom of the scorpion Opisthacanthus madagascariensis, has shown antitumor effects in various cancer cell lines, including breast cancer and chronic myeloid leukemia. However, its hemolytic action limits its potential therapeutic use. This study aims to assess the antitumor and antiproliferative activities of synthetic peptides derived from IsCT1 (IsCT-P, AC-AFPK-IsCT1, AFPK-IsCT1, AC-KKK-IsCT1, and KKK-IsCT1) in the context of oral squamous cell carcinoma. We evaluated the cytotoxic effects of these peptides on tongue squamous cell carcinoma cells and normal cells, as well as their impact on cell cycle phases, the expression of proliferation markers, modulators of cell death pathways, and mitochondrial potential. Our results indicate that the IsCT1 derivatives IsCT-P and AC-AFPK-IsCT1 possess cytotoxic properties towards squamous cell carcinoma cells, reducing mitochondrial membrane potential and the proliferative index. The treatment of cancer cells with AC-AFPK-IsCT1 led to a positive modulation of pro-apoptotic markers p53 and caspases 3 and 8, a decrease in PCNA and Cyclin D1 expression, and cell cycle arrest in the S phase. Notably, contrary to the parental IsCT1 peptide, AC-AFPK-IsCT1 did not exhibit hemolytic activity or cytotoxicity towards normal cells. Therefore, AC-AFPK-IsCT1 might be a viable therapeutic option for head and neck cancer treatment.

Open article ↗

2023-05-11 | Analysis of Expression of RNA Helicases and Cofactors in Human Tissues and Cancer

RNA helicases are ubiquitously expressed enzymes that function as key regulators of many different aspects of gene expression. They use their nucleoside triphosphate-dependent activity to drive the remodeling of various structured RNAs and RNA-protein complexes during their biogenesis and function. In the cellular environment, careful regulation of RNA helicases is critical and many RNA helicases associate with protein cofactors that either stimulate the catalytic activity of the helicase or direct its recruitment to it specific RNA substrates or both. The largest known family of RNA helicases are the so-called G-patch proteins, which are characterized by a glycine-rich domain. More than 20 human G-patch proteins are known, however, the roles of only some of these proteins have been analyzed so far. Due to their central roles in modulating gene expression, dysregulation of RNA helicases and their cofactors is often associated with disease, especially cancer. G-patch protein mRNA expression levels had been analyzed in high-throughput studies in particular cell types, but they had not been compared between different cell types or correlated with protein expression levels. The study aimed at exploring the expression levels on the mRNA and protein level of the human G-patch proteins and G-patch protein-interacting helicases in different cancer cell lines and in matched-pair tissue samples from patients with fibromyxosarcoma in limbs or squamous cell carcinoma in the oral cavity. This could provide a basis for studying the roles of differentially expressed proteins as well as differences in the regulation of RNA helicase functions in tumor cells and in the long term could highlight potential candidates for the development of novel therapeutic approaches. Multiple examples of specifically up- or downregulation of the expression of G-ptach proteins and RNA helicases analyzed could be observed. While many of the findings could be correlated with independent reports from other researchers, the study also highlights several significant changes in gene expression of G-patch proteins, which were not previously reported and can be further investigated in future studies. Since the beginning of the study presented here, the development of NGS technologies has allowed the generation of a large amount of sequencing data giving transcriptome-wide insights into mRNA expression levels in a range of different cell types and tissues. However, significant hits identified by NGS often still required to be confirmed using gene-specific qPCR. As a further outlook, it would be beneficial to conduct high-throughput sequencing analyses of various cancer samples in large sample sizes in comparison to matched-pair normal tissue to alleviate general differences in gene expression levels between individuals. The combination of whole-genome and exome sequencing as well as high-throughput mass spectrometry could provide comprehensive information on gene expression regulation in healthy tissues and in disease.

Open article ↗

antibodies

2026-03-05 | Low-dose nivolumab with neoadjuvant chemotherapy and oral metronomic therapy in borderline resectable oral cavity squamous cell carcinoma: a phase II trial

Background: Non-surgical management of oral cavity squamous cell carcinoma (OSCC) has poorer outcomes compared to surgery. In borderline resectable tumors, historical neoadjuvant chemotherapy achieves surgical conversion in only about 40%. Combining low-dose immunotherapy and oral metronomic therapy (OMT) with chemotherapy may enhance resection rate and survival. Methods: Between April 2023 and April 2024, patients deemed 'borderline resectable' OSCC based on predefined criteria by a multidisciplinary tumor board were prospectively offered this Phase II single-arm interventional trial setting. Patients received two 21-day cycles of carboplatin, nab-paclitaxel, low-dose nivolumab, and six weeks of erlotinib, methotrexate, celecoxib, with additional cycle(s) if needed. Primary endpoint was R0 resection rate. Secondary endpoints were objective response rate, pathologic response, safety, event-free survival (EFS), and overall survival (OS). Immune biomarkers and Volumetric assessment were exploratory endpoints. The trial was prospectively registered in the Clinical Trial Registry of India (CTRI/2023/04/051617). Findings: Of 34 patients, all except one completed planned neoadjuvant therapy. After 2 cycles, 22 (66·6%) had partial response and 11 had stable disease; none progressed. Twenty six underwent surgery; 25 achieved R0 resection (25/33-75·7% conversion). Four of seven remaining patients received additional cycle(s); three subsequently achieved R0 resection. Overall conversion rate was 90·3% (28/31) excluding 2 patients who refused further treatment. Major pathological response occurred in 12 patients (41·4%), including four with pathological complete response. Grade ≥3 toxicities occurred in 5 of 34 patients (14·7%), with no treatment-related deaths. One patient had grade 4 diarrhea with grade 4 acute kidney injury. Interpretation: The NeoLOCUS regimen offers an affordable, outpatient chemo-immunotherapy approach that improves surgical conversion and pathological response in borderline resectable OSCC. Funding: Fluid Research Grant- Christian Medical College, Vellore, India.

Open article ↗

2026-01-01 | Immunoexpression of programmed death receptor 1 and its ligands in oral cavity squamous cell carcinoma

BACKGROUND: This study analyzed the immunoexpression of programmed death receptor 1 and its ligands in oral cavity squamous cell carcinoma and correlated the findings with histomorphological parameters. MATERIAL AND METHODS: Forty cases of oral cavity squamous cell carcinoma (10 in the floor of the mouth, 10 in the palate, 10 in the lower lip, and 10 in the tongue) were selected. The percentages of cytoplasmic/membrane immunopositivity for programmed death receptor 1 and its ligands in neoplastic and stromal cells were evaluated at the tumor invasion front. RESULTS: Programmed death-ligand 1 presented high immunoexpression in all subsites, especially at the parenchyma level. Compared to floor of the mouth and palate, lower lip and tongue exhibited higher expression of programmed death receptor 1 and programmed death-ligand 2 in parenchymal cells and of programmed death receptor 1 in stromal cells, with statistically significant differences for programmed death receptor 1 expression in lower lip (p<0.05). Tongue presented the highest median percentages of positivity for programmed death-ligand 2, with statistically significant differences when compared to floor of the mouth (neoplastic cells and stromal cells) and lower lip (stromal cells) (p<0.05). Regarding histomorphological aspects, the inflammatory infiltrate appears to be an important factor for the immunoexpression of these proteins in oral cavity squamous cell carcinoma. CONCLUSIONS: The study suggests location-dependent differences in the antitumor immune response to oral cavity squamous cell carcinoma. Inflammatory infiltrate is key to protein immunoexpression. These findings are crucial for developing new immunotherapeutic strategies for oral cancer.

Open article ↗

2025-12-26 | Nivolumab added to cisplatin and radiotherapy versus cisplatin and radiotherapy alone after surgery for people with squamous cell carcinoma of the head and neck at a high risk of relapse (GORTEC 2018-01 NIVOPOST-OP): a randomised, open-label, phase 3 trial.

Postoperative cisplatin and radiotherapy is the standard of care for high-risk resected locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). The NIVOPOST-OP trial aimed to assess the efficacy and safety of programmed death 1 blockade by nivolumab added to cisplatin and radiotherapy in this setting. This open-label, phase 3 trial evaluated adding nivolumab to cisplatin and radiotherapy after surgery for LA-SCCHN with high-risk pathological features. The main inclusion criteria were age 19-74 years, an Eastern Cooperative Oncology Group performance status 0-1, squamous cell carcinoma of the oral cavity, oropharynx, larynx, or hypopharynx resected with macroscopic complete resection, and at least one high-risk pathological feature: nodal extracapsular extension, microscopically positive margins, four or more cervical nodal involvements without extracapsular extension, and multiple perineural invasions. 680 participants recruited in 82 sites across six countries (France, Spain, Poland, Belgium, Greece, and Switzerland) were randomly assigned 1:1 to receive cisplatin and radiotherapy (66 Gy, cisplatin 100 mg/m2 intravenously once every 3 weeks, for three cycles); or nivolumab 240 mg intravenously, followed by cisplatin and radiotherapy with three cycles of concomitant nivolumab 360 mg once every 3 weeks, and six cycles of adjuvant nivolumab 480 mg once every 4 weeks. The primary endpoint was disease-free survival as per investigator assessment in the intention-to-treat population. 230 disease-free survival events (relapses or deaths) were required to detect a hazard ratio of 0·65 with 0·05 two-sided α error, with 90% power. The trial is registered at ClinicalTrials.gov (NCT03576417) and is active, but not recruiting. The 680 patients were recruited from Oct 15, 2018, to July 3, 2024. The analysis was based on 666 participants randomly assigned until the cutoff date (April 30, 2024), at which point the required number of events was reached (median follow-up 30·3 months). Disease-free survival was significantly improved with nivolumab, cisplatin, and radiotherapy versus cisplatin and radiotherapy alone, irrespective of programmed death ligand 1 expression (HR 0·76; 95% CI 0·60-0·98; stratified log-rank test p value=0·034). There was an increase in the rate of participants with treatment-related grade 4 adverse events with nivolumab, cisplatin, and radiotherapy compared with cisplatin and radiotherapy (30 [10%] of 312 vs 16 [5%] of 306). Treatment-related deaths occurred in two participants in each group. Nivolumab added to cisplatin and radiotherapy in high-risk resected LA-SCCHN improves disease-free survival with moderate toxic effect increase, and can be proposed as a new standard treatment. Groupe Oncologie Radiotherapie Tete Et Cou (GORTEC) and Bristol Myers Squibb.

Open article ↗

2025-11-24 | Streptococcus spp. in oral cancer: host-microbe interactions, mechanistic insights, and diagnostic implications

Cancers of the oral cavity, particularly the widely prevalent oral squamous cell carcinoma, are associated with microbial dynamics within the oral niche. Among them, oral Streptococcus sp. - once neglected as a commensal habitat of the oral cavity - is currently highlighted for its pivotal dual interplay in the progression and suppression of oral cancers. In this comprehensive review, we describe the association of these oral streptococcal species with oral cancer in detail - right from their abundance and depletion during the progression of the disease, mechanistic synergy involving factors such as the surface receptors playing an intricate role in biofilm and co-adhesion strategies, to the inflammatory interplay in cancerous cells, and metabolic reprogramming associated with oral cancer. We also highlight oncogenic and onco-mitigating oral streptococci as biomarkers, observing a complex microbial interaction regulating tumor initiation and development. This review serves as a novel direction to address streptococcal mediators in oral cancer by bridging research gaps in mechanistic evidence and proposing effective prospects that can address deeper exploration of streptococcal dualistic role in the tumor microenvironment to decipher effective theragnostic strategies to manage oral cancer.

Open article ↗

2025-11-01 | A prospective comparative randomized study to asses local control and toxicity in patients with intermediate risk oral cavity squamous cell carcinoma with post-operative adjuvant radiotherapy with or without cetuximab

Background: Treatment of oral cavity cancer includes surgery, radiotherapy (RT), chemotherapy, and immunotherapy. Surgery followed by adjuvant RT plays an important role in patients with intermediate risk factors but many studies showed locoregional failure following adjuvant RT alone. Elevated epidermal growth factor receptor (EGFR) expression is detected in 90% of patients with head and neck squamous cell carcinoma (SCC). Aims and Objectives: The objective of this study was locoregional disease control, toxicities, disease-free survival (DFS), and OS between post-operative only RT and concurrent cetuximab (CP) with RT in oral cavity SCC with intermediate risk factors. Materials and Methods: Arm A received adjuvant RT at a dose of 60 Gy by 30 fractions, total 6 weeks duration. In study arm B received the same dose of adjuvant RT as study arm A along with concomitant injection of cetuximab at a dose of 400 mg/m2 prior to start of RT and then 250 mg/m2 weekly. Results: In arm A, 14 (56.0%) and arm B, 14 (56.0%) patients had anterior 2/3rd of tongue and buccal mucosa cancer, respectively. In arm A, 15 (60.0%) and arm B, 12 (48.0%) patients had pT2 status, respectively. There was no rash in arm A but 9 (36%) patients developed rash in arm B. DFS at 12 months was higher in CP arm B compared to arm A but not statistically significant. Conclusion: This study showed addition of CP to RT improved LRC with increased and manageable adverse effects.

Open article ↗

other

2025-05-28 | VERSATILE-003: A phase 3, randomized, open-label trial of PDS0101 and pembrolizumab compared with pembrolizumab for first-line treatment of patients with HPV16-positive recurrent/metastatic head and neck squamous cell carcinoma.

TPS6111 Background: Human papillomavirus (HPV)-related head and neck squamous cell carcinoma (HNSCC) has surpassed cervical cancer as the most common HPV-related cancer in the US, with the majority being caused by HPV16. Persistent expression of HPV16 oncoproteins E6 and E7 by host genome may promote HNSCC. HPV16-positive HNSCC may be associated with poor clinical outcomes in the recurrent/metastatic (R/M) setting. PDS0101 (Versamune HPV) is an HPV16-immunotherapy that generates a potent, targeted T cell attack against HPV16 E6 & E7. In a Phase 2 study, PDS0101 plus pembrolizumab has shown encouraging safety and survival benefit in patients with HPV16-positive R/M HNSCC. (Weiss J et al. ESMO 2024. Poster 879P. NCT04260126). Methods: VERSATILE-003 is a global Phase 3, randomized, controlled, open-label study evaluating PDS0101 plus pembrolizumab vs. pembrolizumab in patients with HPV16-positive R/M HNSCC with PD-L1 positive disease (CPS ≥1). Key eligibility criteria include age ≥18-years-old, histologically- or cytologically-confirmed diagnosis of R/M HNSCC with primary tumor location of oropharynx, oral cavity, hypopharynx, or larynx and no prior systemic anticancer treatment in the R/M setting, HPV16 tumor positivity (centrally tested), PD-L1 positivity defined as CPS ≥ 1 using FDA-approved PD-L1 IHC 22C3 pharmDx kit, and measurable disease based on RECIST 1.1 confirmed by blinded independent central review (BICR). Patients will be randomized 2:1 to receive pembrolizumab 200 mg IV Q3W with PDS0101 1 mL SC administered concurrently during Cycles 1, 2, 3, 4, and 12 (investigational arm), or pembrolizumab 200 mg IV Q3W alone (control arm). The primary objective is to compare overall survival (OS) between the investigational and control arms. Secondary objectives include objective response rate (ORR), disease control rate (DCR), duration of response (DOR), and progression-free survival (PFS) using RECIST 1.1 and assessed by BICR. Exploratory objectives include tumor response assessed by investigator and by irRECIST, PFS2, quality of life as assessed by EQ-5D, QLQ-C30, and QLQ H&N35, and assessment of ctHPVDNA. Updated enrollment data will be provided. Clinical trial information: NCT06790966 .

Open article ↗

2025-05-28 | Randomized phase I trial of adjuvant personalized cancer vaccine TG4050 in resected locally advanced (LA) head and neck squamous cell carcinoma (HNSCC) patients (pts).

6016 Background: Approximately one third of pts with resected LA HNSCC recur. T-cells targeting tumor specific mutations drive anti-tumor immune responses. TG4050 is a viral-based personalized cancer vaccine, encoding up to 30 tumor-specific DNA sequences bearing in-silico predicted class I and class II epitopes. We hypothesized that TG4050 prime an adaptive immune response against tumor antigens and prevent relapse in pts with resected LA HNSCC after treatment with curative intent ( NCT04183166 ). Methods: The multicenter, open label, randomized, 2-arm Phase I trial evaluated TG4050 in LA HNSCC pts achieving complete remission following surgery and adjuvant radiotherapy +/- chemotherapy. Pts were randomized to receive (Arm A) weekly doses of TG4050 for 6 weeks followed by a maintenance period of one dose every 3 weeks for up to 20 doses or no vaccine (Arm B, vaccination at relapse in combination with SOC). Safety, efficacy and immunogenicity were evaluated. In selected pts, exploratory characterization of the T cell response was performed using tetramer staining, bulk and single-cell (sc)TCR sequencing. Results: 33 pts were randomized between January 2021 and April 2023, 17 pts to Arm A and 16 pts to Arm B. Median age was 61 years (26-79 years), tumor location was oral cavity in 24 pts (72.7%), hypopharynx and oropharynx in 4 pts (12.1%), respectively and larynx in one pt (3.0%). TG4050 was safe and well tolerated with only grade 1 or 2 treatment-related adverse events (AEs). The most frequently reported were injection site reactions. After a median follow-up of 28.5 months, all 16 pts receiving TG4050 in Arm A remained disease-free whereas 3 out of 16 pts in Arm B relapsed. Disease Free Survival (DFS) data at 24 months for all patients will be presented. Exploratory qualitative analyses of the neoantigen-specific T cell response by ELISpot were presented previously. In-depth characterization of the neoantigen-specific T cells including clonal expansion by TCR sequencing and longitudinal analysis by tetramer staining will be presented. Conclusions: TG4050 is safe and induces immune responses in pts with resected LA HNSCC. No relapse occurred in the vaccine arm as opposed to 19% in the control arm. With the evolution of the landscape, adjuvant anti-PD1 therapy may become standard in resected LA HNSCC. TG4050 warrants further evaluation in combination with anti-PD1 therapy in phase III trials. Clinical trial information: NCT04183166 .

Open article ↗

2025-02-27 | Tetrahedral-DNA-Nanostructure-Modified Engineered Extracellular Vesicles Enhance Oral Squamous Cell Carcinomas Therapy by Targeting GPX4

Oral squamous cell carcinoma (OSCC) represents a heterogeneous group of malignancies originating from the mucosal lining of the oral cavity. Current treatment modalities primarily involve surgery, chemotherapy, and radiotherapy. Despite the use of multimodal therapy, the 5 year overall survival rate for OSCC remains around 50%, underscoring the need for the development of nontoxic agents with potent antitumor activity. Extracellular vesicles (EVs) are nanoscale, membrane-bound structures that can selectively deliver small molecules, nucleic acids, and proteins to target cells, making them a promising platform for drug delivery in cancer therapy. Strategies to improve the uptake of EVs and enhance the delivery of therapeutic molecules to target cells are critical for advancing precision medicine. Tetrahedral DNA nanostructures (TDNs) have shown significant potential in facilitating drug endocytosis and delivery, as well as improving tissue penetration. In this study, TDN@EVs were conducted by modifying the membrane surface of M1-EVs with TDNs, which demonstrated improved biological stability and drug delivery efficiency compared to unmodified EVs. In vitro and in vivo experiments showed that TDN@EVs significantly inhibited OSCC cell proliferation and migration while promoting apoptosis. TDN@EVs exhibited superior drug penetration properties, further amplifying their antitumor effects. Proteomic analysis identified Hsc70 as the key protein responsible for the antitumor activity of the TDN@EVs. The efficient delivery of Hsc70 into tumor cells by TDN@EVs led to the degradation of GPX4, inducing ferroptosis, mitochondrial stress, and DNA damage in tumor cells. These findings highlight the potential of TDN@EVs as an effective and safe approach for cancer therapy. In conclusion, TDN@EVs present as a promising effective strategy for the targeted delivery of therapeutic agents in OSCC treatment, offering enhanced biological stability, efficient drug delivery, and significant antitumor effects.

Open article ↗

2024-12-30 | Targeted CRISPR/Cas9 Lipid Nanoparticles Elicits Therapeutic Genome Editing in Head and Neck Cancer

Squamous cell carcinomas of the head and neck (HNSCC) originate in the upper aerodigestive tract, including the oral cavity, pharynx, and larynx. Current treatments of locally advanced HNSCC often lead to high treatment failure, and disease recurrence, resulting in poor survival rates. Advances in mRNA technologies and lipid nanoparticle (LNP) delivery systems led to several clinical trials involving LNP-CRISPR-Cas9 mRNA-based therapeutics. Despite these advances, achieving cell-type-specific extrahepatic mRNA delivery is still challenging. This study introduces a safe and effective intratumoral EGFR-targeted CRISPR-LNP delivery strategy for knocking out SOX2, which is a cancer-specific gene. To assess their therapeutic potential, it is shown that LNPs made from ionizable lipids with helper lipids co-encapsulating Cas9 mRNA and sgRNA targeting SOX2 (sgSOX2), lead to a ≈60% reduction in HNSCC cell viability in vitro. Next, using a xenograft HNSCC mouse model, targeted delivery of 𝜶EGFR- CRISPR-sgSOX2-LNPs to HNSCC cells resulted in a 90% inhibition of tumor growth and a 90% increase in survival for > 84 days, with tumor disappearance observed in 50% of the mice. These findings emphasize the potential of targeted mRNA-Cas9-LNPs in clinically accessible solid tumors, specifically in reaching tumor cells and inducing persistent therapeutic responses in tumors with high-recurrence rates like HNSCC.

Open article ↗

2024-09-18 | The future of interleukin gene therapy in head and neck cancers

Head and neck cancer (HNC), primarily head and neck squamous cell carcinomas, originates from the squamous epithelium in areas like the oral cavity, lip, larynx, and oropharynx. With high morbidity impacting critical functions, combined treatments like surgery, radiation, and chemotherapy often fall short in advanced stages, highlighting the need for innovative therapies.

Open article ↗