small molecules

2026-05-28 | ERBIOTAX (TTCC-2022-02): A phase II, multicenter, randomized study of cetuximab with or without weekly paclitaxel after progression on first-line pembrolizumab plus platinum/5-FU in recurrent or metastatic head and neck squamous cell carcinoma.

TPS6131 Background: Pembrolizumab, with or without platinum–5FU (PF), is the current first-line (1L) standard of care for PD-L1–positive recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN). However, no established standard of care exists after progression on immune checkpoint inhibitors (ICI). Emerging evidence suggests that cetuximab administered post-ICI achieves higher objective response rates (ORR) and longer progression-free (PFS) and overall survival (OS) compared with historical second-line (2L) cetuximab outcomes from the pre-ICI era. We hypothesize that 2L treatment with cetuximab +/- paclitaxel may be more effective after ICI failure than previously observed in the pre-ICI era. Methods: This is a multicenter, open-label, randomized, non-comparative, two-arm, investigator-initiated phase 2 trial. Patients will be randomized (2:1) to cetuximab plus paclitaxel (Arm A: ERBITAX) or cetuximab monotherapy (Arm B), administered on Days 1, 8 and 15 of 21-day cycles for 4 cycles, followed in both arms by biweekly cetuximab monotherapy until disease progression, death, unacceptable toxicity, or withdrawal of consent. A total of 65 evaluable patients will be enrolled: 41 in Arm A (H0: ORR 25%, H1: 45%, 80% power, two-sided alpha 0.05) and 24 in Arm B (H0: ORR 10%, H1: 30%, 80% power, two-sided alpha 0.05). The primary endpoint is ORR in each arm. Secondary endpoints include disease control rate (DCR), PFS, OS, health-related quality of life (EORTC QLQ-C30, EORTC QLQ-H&N35 and EuroQol EQ-5D) and safety. Baseline tumor tissue (all patients) and on-treatment samples (between cycles 2-5 in 50% of patients; optionally at progression), as well as serial plasma samples will be collected for translational exploratory studies. Patients must have histologically confirmed SCCHN of oral cavity, oropharynx (HPV-positive or HPV-negative), hypopharynx, or larynx, with confirmed progression per RECIST 1.1. on or after 1L pembro + PF. The study started enrollment in June 2025, with 7 patients enrolled by December 23, 2025. The total accrual period is 18 months. Clinical trial identifiers: NCT06856213; EUDRACT 2024-514953-31-00. Trial supported by Merck, S.L.U., Madrid, Spain, an affiliate of Merck KGaA, Darmstadt, Germany, providing study medication and financial support. Clinical trial information: NCT06856213 .

Open article ↗

2026-05-28 | A phase II trial of a novel induction regimen: Polymeric micellar paclitaxel plus cisplatin for locally advanced head and neck squamous cell carcinoma.

e18067 Background: Induction chemotherapy with the TPF regimen is recommended by international guidelines for locally advanced head and neck squamous cell carcinoma. However, its significant toxicities lead to generally poor patient tolerance, limiting its widespread clinical application, particularly among elderly or medically unfit patients. By encapsulating paclitaxel within micelles, pm-Pac enhanced permeability and retention effect, thereby improving pharmacokinetics and tumor-targeted delivery. This study evaluated the efficacy and safety of induction therapy with polymeric micellar paclitaxel plus cisplatin in LA-SCCHN, aiming to determine whether its pharmacologic advantages translate into clinical benefit. Methods: According to clinical trail the Eligible patients were stage III to IVB HNSCC received polymeric micellar paclitaxel 230 mg/m² (Day 1) plus cisplatin 70 mg/m² (Day 1–2) every three weeks for 2–4 cycles. The primary endpoint was objective response rate (ORR). Secondary endpoints included disease control rate (DCR), safety, adverse events (AEs), and completion of subsequent definitive therapy. Results: Thirty patients were enrolled (median age, 66 years), including five HPV-positive cases (16.7%). After induction therapy, 5 patients achieved complete response (CR) and 11 achieved partial response (PR), yielding an ORR of 53.3% and a DCR of 93.3%. ORR reached 80% in HPV-positive patients versus 48% in HPV-negative/unknown patients. Common AEs included myalgia/limb pain (60%), neutropenia (26.7%), and bone marrow suppression (33.3%). Grade ≥3 AEs were mainly hematologic; no solvent-related hypersensitivity reactions occurred. Conclusions: Polymeric micellar paclitaxel plus cisplatin demonstrated promising antitumor activity, high disease control, and favorable tolerability in patients with LA-SCCHN, particularly among elderly or TPF-intolerant individuals. Clinical trial information: ChiCTR2500110591. Variable Number (n=30) Percentage (%) Age, years Median 66 (range 35–77) — <65 12 40.0 ≥65 18 60.0 Sex Male 23 76.7 Female 7 23.3 Primary Tumor Site Hypopharynx 9 30.0 Larynx 8 26.7 Oropharynx 6 20.0 Oral cavity 4 13.3 Other* 3 10.0 Clinical Stage II 2 6.7 III 13 43.3 IVA 14 46.7 IVB 1 3.3 HPV Status Positive 5 16.7 Negative/Unknown 25 83.3 Response Number (n=30) Percentage (%)

Open article ↗

2026-05-27 | Phase IIa study of tosposertib, a dual TGFβRI and VEGFR2 inhibitor, in combination with pembrolizumab in recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC).

2635 Background: Tosposertib (TU2218) is a highly potent dual inhibitor of the transforming growth factor-β type I receptor (TGFβRI/ALK5) and vascular endothelial growth factor receptor 2 (VEGFR2), designed to simultaneously target immunosuppressive tumor microenvironment signaling and angiogenesis. This open-label, multicenter, non-randomized phase IIa trial evaluated the efficacy and safety of tosposertib in combination with pembrolizumab in patients with R/M HNSCC (NCT05784688). Methods: Eligible patients included anti–PD-(L)1–naïve patients with PD-L1 combined positive score (CPS) ≥1. Tosposertib (97.5 mg twice daily; 2 weeks on/1 week off) was administered orally in combination with pembrolizumab (200 mg intravenously every 3 weeks). Results: As of December 31, 2025, 29 patients (median age, 61 years; 76% male) had been enrolled, with a median follow-up duration of 6.0 months (range, 8–401 days). Primary tumor sites included the oral cavity (n=11, 37.9%), oropharynx (n=6, 20.7%), larynx (n=3, 10.3%), and nasal/paranasal regions (n=3, 10.3%). HPV positivity was observed in 13.8% (4/29) of patients. Among 26 efficacy-evaluable patients, responses were assessed by treatment line. In the first-line setting, 9 of 12 patients achieved an objective response (ORR, 75.0%), including 1 confirmed complete response (CR) and 8 partial responses (PRs; 6 confirmed, 2 unconfirmed). Among the 14 patients who had received at least one prior systemic therapy, the ORR was 42.9%, with 1 confirmed CR and 5 confirmed PRs. A numerically higher ORR was observed in patients with PD-L1 CPS ≥20 compared with those with CPS 1–10 (66.7% vs 52.9%). The most frequent any-grade treatment-emergent adverse events (TEAEs), (≥20%) [and ≥ Gr3 TEAEs], were rash (48.3% [20.7%]), mucosal inflammation (34.5% [13.8%]), pruritus (27.6% [3.4%]), weight loss (27.6% [0%]), and elevations in aspartate aminotransferase (AST; 20.7% [3.4%]) or alanine aminotransferase (ALT; 20.7% [3.4%]). Discontinuations due to TEAEs occurred in three patients. No treatment-related deaths were reported. Conclusions: Tosposertib in combination with pembrolizumab demonstrated a manageable safety profile and encouraging antitumor activity in patients with R/M HNSCC, with particularly robust efficacy observed in the first-line setting and a favorable trend in PD-L1–high tumors. Clinical trial information: NCT05784688 . Best overall response by subgroups. Best Overall ALL(n=26) Prior lines of therapy Prior lines of therapy PD-L1status, n (%) PD-L1status, n (%) Response, n (%) None(n=12) ≥1(n=14) CPS 1-19(n=17) CPS ≥20(n=9) Complete Response 2 (7.7) 1 (8.3) 1 (7.1) 1 (5.9) 1 (11.1) Partial Response 13 (50.0) 8 (66.7) 5 (35.7) 8 (47.1) 5 (55.6) Stable Disease 5 (19.2) 2 (16.7) 3 (21.4) 3 (17.6) 2 (22.2) Progressive Disease 6 (23.1) 1 (8.3) 5 (35.7) 5 (29.4) 1 (11.1) Response Rate (%) 57.7 75.0 42.9 52.9 66.7

Open article ↗

2026-04-01 | Biomarkers & Survival in Head and Neck Squamous Cell Carcinoma: A Systematic Review & Meta‐Analysis

Abstract Objective EGFR, cyclin D1, and Bcl‐2 are proteins involved in different stages of tumorigenesis which have all been associated with poor prognosis in head and neck squamous cell carcinoma (HNSCC). In this systematic review and meta‐analysis, we aim to measure the association of each protein with survival in HNSCC. Data Sources PubMed, Scopus, and Cochrane databases. Review Methods A systematic review of EGFR, cyclin D1, and Bcl‐2 was conducted to determine the association between overexpression and survival in HNSCC. A weighted random‐effects meta‐analysis then measured pooled rates of overall, disease‐free, and disease‐specific survival for each protein. Results Overexpression of EGFR was associated with worse overall mortality (HR = 1.52, P = .01), disease‐related mortality (HR = 1.33, P = .02), and disease progression (HR = 1.99, P < .001). Overexpression of cyclin D1 was also associated with worse overall mortality (HR = 1.93, P < .001), disease‐related mortality (HR = 1.57, P = .01), and disease‐specific mortality (HR = 1.93, P = .01). The association between cyclin D1 and overall mortality also remained significant in papers examining only oropharynx cancer (HR = 2.66, P = .03). Overexpression of Bcl‐2 was associated with worse overall mortality (HR = 1.92, P = .002). Conclusion These findings support EGFR, cyclin D1, and Bcl‐2 as biomarkers which portend worse prognosis in HNSCC. Further work will be needed to understand whether measurement of these proteins can be useful in tailoring treatment strategies, and whether they can be used as targets for novel therapies.

Open article ↗

2026-03-30 | OVER-ALL RESPONSE OF INDUCTION CHEMOTHERAPY IN PATIENTS OF LOCALLY ADVANCED SQUAMOUS CELL CARCINOMA OF THE ORAL CAVITY, OROPHARYNX, AND LARYNX AT ONCOLOGY DEPARTMENT JINNAH HOSPITAL, LAHORE

Background: Oral cavity, oropharynx, and larynx locally advanced squamous cell carcinoma (SCC) poses a great therapeutic challenge because of heavy tumor burden and functional impairment. Induction chemotherapy (IC) is becoming an increasingly popular way of downstaging tumors and enhancing the treatment. The purpose of this research was to assess the response to the induction chemotherapy in general in the patients of the Jinnah Hospital, Lahore, with locally advanced SCC. Objective: To identify the Over-all response of induction chemotherapy in patients with locally advanced squamous cell carcinoma of the oral cavity, Oropharynx and larynx in Jinnah Hospital, Lahore. Methods: This case series was a descriptive case series done in Oncology Department of Jinnah Hospital, Lahore from November 2025 to February 2026. Non-probability consecutive sampling was used to enroll 87 chemotherapy-naïve patients aged 1870 years with Stage III-IV SCC and ECOG performance status of 0-2. The patients were treated with induction chemotherapy consisting of carboplatin (AUC 3) and paclitaxel (125mg/m 2) after every two weeks during three cycles. At the 13th week, the response of tumors was evaluated through contrast-enhanced CT scans based on the criteria of RECIST 1.1. ORR was determined as the percentage of patients who had a complete response (CR) or partial response (PR). Results: Tumor responses were categorized as CR, PR, stable disease (SD), and progressive disease (PD). The overall response rate (CR + PR) was analyzed along with stratification for age, gender, tumor site, stage, and ECOG status. Statistical analysis was performed using SPSS version 26, and associations were assessed using the Chi-square test. Conclusion: Induction chemotherapy is shown to have a high overall response rate in patients with locally advanced SCC of the oral cavity, oropharynx and larynx, and therefore induction chemotherapy is an effective neoadjuvant treatment modality in clinical practice.

Open article ↗

cell therapies

2025-10-23 | Multiomic Selection of Cancer-Testis Antigens as Precision Immuno-oncologic Targets in Head and Neck Cancer

Importance Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignant neoplasm with an increasing need for precision therapeutics. Cancer-testis antigens (CTAs) represent promising targets given their aberrant tumor expression and otherwise localized expression to immune-privileged tissues with no (testis-restricted) or minimal (testis-selective) expression in other human body sites. Despite their potential, limited studies rigorously evaluate CTAs as therapeutic targets in HNSCC. Objective To orthogonally validate and present specific CTAs as potential precision immuno-oncologic targets in both previously untreated (de novo) and recurrent HNSCC tumors. Design, Setting, and Participants This was a cross-sectional study conducting multiomic analyses on a single academic tertiary care center’s tumor registry from 2018 to 2023, with validation using publicly available transcriptomic datasets. A total of 33 tumor samples from patients with HNSCC, including both de novo and radiation-recurrent tumors, were analyzed. Data were analyzed from August to December 2024. Main Outcomes and Measures The primary outcome was the identification and rigorous validation of specific CTAs with tumor-specific expression in HNSCC. Results This study analyzed 33 HNSCC institutional tumor specimens, including 25 de novo and 8 radiation-recurrent tumors. Of 33 included patients, 25 (76%) were male, 8 (24%) were female, and the median (range) age was 61 (29-87) years. Tumor subsites included the oral cavity (24 [73%]), larynx (7 [21%]), and oropharynx (2 [6%]). Tumors were primarily T4a (23 [70%]), with nodal involvement in 16 (48%). Initial analysis of bulk RNA-sequenced institutional data and single-cell RNA-sequenced external data identified several CTAs ( DKKL1 , SPANXB1 , SPANXD , and ACTL8 ) upregulated in recurrent tumors. An expanded reanalysis revealed that CTAs were expressed across HNSCCs, including robust expression not only in radiation-recurrent disease but also in de novo tumors. Immunohistochemistry was performed on ACTL8 to confirm transcriptional level findings at the protein level, which showed moderate focal cytoplasmic staining in tumor tissue. To refine the tumor-specific CTA list, an exclusionary analysis using single-cell RNA-sequenced data from normal oral mucosa was conducted, removing any CTAs with any expression in normal tissue. This resulted in a final list of 23 testis-restricted and 44 testis-selective CTAs specific to HNSCC, of which 14 CTAs overlapped across all transcriptomic datasets. Finally, using CopyKAT, CTAs were specifically enriched in malignant epithelial populations compared with benign populations within the same patients with HNSCC. Conclusions and Relevance In this study, a set of 23 testis-restricted and 44 testis-selective CTAs were orthogonally validated in multiple tumor datasets. Of these, a core set of 14 CTAs were consistently detected across all datasets. Their tumor specificity and broad expression bolster their potential as promising precision immuno-oncologic targets for future T-cell receptor engineering efforts.

Open article ↗

2025-04-25 | Abstract CT058: Final results of a first-in-human (FIH) study of intratumoral pan-ErbB-targeted CAR-T cell therapy for head and neck squamous cell carcinoma (HNSCC): T4 immunotherapy

Abstract Background: Advanced HNSCC has a dismal prognosis despite multiagent treatment. Epidermal growth factor receptor (EGFR, ErbB-1) is upregulated in most tumors, although EGFR-targeted therapy yields modest benefit. Other ErbB family members are commonly co-expressed, providing a rationale for targeting of the extended ErbB network in HNSCC. We present final toxicity and response data for this FIH dose escalation trial of intratumorally administered pan-ErbB-targeting CAR-T cells (T4 immunotherapy) in patients (pts) with advanced HNSCC. Methods: Eligible pts had locally advanced, recurrent or metastatic HNSCC (excluding brain), accessible tumor site(s) for T4 administration and radiologically measurable disease. Peripherally harvested T cells were transduced to co-express pan-ErbB-targeting CAR T1E28ζ and chimeric IL-4/IL-2 receptor 4αβ. Cells were expanded ex vivo in IL-4 to generate T4 immunotherapy, which was injected as a fresh product into single or multiple locoregional tumor sites. Doses ranged from 1×107 to 1×109 cells across 7 cohorts, using 3+3 dose escalation in cohorts 1-5. Cohorts 6 and 7 received 1×108 cells preceded by lymphodepleting (LD) cyclophosphamide and fludarabine chemotherapy. Cohort 7 received additional nivolumab 480mg q4w for 3 cycles. Primary endpoint was dose limiting toxicity (DLT) within 28d. Secondary endpoints included radiologic response at 6w, presence of tumoral and circulating T4+ T cells and serum and tumoral immunomodulatory markers. Results: 19 pts (median age, 62; M:F,15:4) received T4 immunotherapy: 3 in each cohort 1-6 and 1 in cohort 7. Site of origin was oral cavity in 11 (57.9%), oropharynx, 4 (21.1%); nasopharynx, 2 (10.5%); hypopharynx and occult primary 1 each (5.3%). Pts had received a median of 2 (1-5) prior treatment lines. No DLTs were observed. All pts experienced TRAEs, largely G1/2; most common were local swelling, pain or infection, fever, CRS, chills, fatigue and nausea, with cytopenias in LD cohorts. Of 4 instances of CRS, 3 were G1 and 1 was G2. At 6 weeks, 10 pts (52.6%) had stable disease and 9 (47.4%) had progressed, with no association with T4 dose, LD or nivolumab. There were no radiologic responses though softer tumor consistency was noted in several pts. Median overall survival (mOS) was &gt;10m. Subsequent treatments included palliative radiotherapy, chemotherapy +/- cetuximab, electrochemotherapy or trial in 8 pts; no treatment, 4; unknown, 3. One pt had a durable complete response to subsequent local injection of talimogene laherparepvec with pembrolizumab. Conclusions: Intratumoral pan-ErbB-directed CAR-T cell injection was well tolerated and associated with disease stability in heavily pretreated HNSCC. mOS was longer than that expected for this cohort. The lack of radiologic responses highlights the need for improved advanced cell therapies for solid tumors. Citation Format: Cienne Morton, Fiona Wang, Sophie Papa, Antonella Adami, Michael Metoudi, Daniela Achkova, Fiona Reid, Maria Elstad, Nicholas Beckley-Hoelscher, Abdel Douiri, Marc Delord, Mike Lyne, Dharshene Shivapatham, Aysar Al-Rawi, Christopher Fisher, Andrew Hope, Sakina Gooljar, Arindam Mitra, Linda Gomm, Ana C. Parente-Pareira, David M. Davies, Farzin Farzaneh, Teresa Guerrero-Urbano, Jean-Pierre Jeannon, James Spicer, John Maher. Final results of a first-in-human (FIH) study of intratumoral pan-ErbB-targeted CAR-T cell therapy for head and neck squamous cell carcinoma (HNSCC): T4 immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT058.

Open article ↗

2023-11-30 | Post-radiation xerostomia therapy with allogeneic mesenchymal stromal stem cells in patients with head and neck cancer: study protocol for phase I clinical trial

Xerostomia is a common side effect of radiotherapy in patients with head and neck tumors that negatively affects quality of life. There is no known effective standard treatment for xerostomia. Here, we present the study protocol used to evaluate the safety and preliminary efficacy of allogeneic mesenchymal stromal stem cells (MSCs) derived from umbilical cord tissue.Ten oropharyngeal cancer patients with post-radiation xerostomia and no evidence of disease recurrence 2 or more years after (chemo)irradiation (intervention group) and 10 healthy volunteers (control group) will be enrolled in this nonrandomized, open-label, phase I exploratory study. MSCs from umbilical cord tissue will be inserted under ultrasound guidance into both parotid glands and both submandibular glands of the patients. Toxicity of the procedure will be assessed according to CTCAE v5.0 criteria at days 0, 1, 5, 28, and 120. Efficacy will be assessed by measuring salivary flow and analyzing its composition, scintigraphic evaluation of MSC grafting, retention, and migration, and questionnaires measuring subjective xerostomia and quality of life. In addition, the radiological, functional, and morphological characteristics of the salivary tissue will be assessed before, at 4 weeks, and at 4 months after the procedure. In the control group subjects, only salivary flow rate and salivary composition will be determined.The use of allogeneic MSCs from umbilical cord tissue represents an innovative approach for the treatment of xerostomia after radiation. Due to the noninvasive collection procedure, flexibility of cryobanking, and biological advantages, xerostomia therapy using allogeneic MSCs from umbilical cord tissue may have an advantage over other similar therapies.

Open article ↗

2018-09-03 | Combination of submandibular salivary gland transfer and intensity‐modulated radiotherapy to reduce dryness of mouth (xerostomia) in patients with head and neck cancer

Abstract Background Xerostomia is a debilitating side effect of radiotherapy for head and neck cancer. Combining surgical submandibular‐gland transfer (SMGT) with intensity‐modulated radiotherapy (IMRT) may provide greater protection of salivary function. Methods This was a single‐institution, prospective phase II feasibility trial. Patients with head and neck cancer or unknown primary with neck node metastases received primary surgery with SMGT and postoperative radiotherapy with tomotherapy (60 Gy in 30 fractions). Toxicity and quality of life (QOL) were assessed before surgery, before RT, and after RT. Results Forty patients received SMGT and IMRT. Only 1 patient experienced grade 3 salivary gland toxicity. At 12 months post‐RT, the rate of absent or only mild xerostomia was 89%, and salivary flow rates were approximately 75% of pre‐RT levels. Conclusions The combination of IMRT with SMGT is feasible and with improved dose constraints may maximally spare the parotid and submandibular glands, leading to decreased xerostomia and improved patient QOL.

Open article ↗

2017-09-05 | Presentation of a variation of the chorioallantoic membrane set up as a potential model for individual therapy for squamous cell carcinoma of the oropharynx

The chorioallantoic membrane of fertilized chicken eggs in an early phase of breeding presents an approved test situation for the growth and treatment of human cancer cells. These models work due to the inoculation of cells into the membrane that stays within the egg shell during the time of invest igation. In this study a modification of this model is presented. Samples of native tumors, rather than cell lines, are transplanted into the membrane and the body of the egg is taken out of the shell and placed in a plastic bowl. These modifications lead to an enhanced accessibility to the chorioallantoic membrane and the surrounding vessels thus facilitating intra venous access and application of pharmaceuticals and a focused radiotherapy. With the current modifications the embryo was kept alive and additionally, the vascularized tumor environment was preserved.

Open article ↗

antibodies

2026-08-15 | Durable Complete Response Following Nivolumab Discontinuation in Human Papillomavirus (HPV)-Positive Oropharyngeal Carcinoma Complicated by Bullous Pemphigoid: A Case Report.

Immune checkpoint inhibitors have improved outcomes in recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), although durable complete responses (CRs) remain uncommon. The optimal duration of immunotherapy is not yet established. We report the case of a 69-year-old female smoker diagnosed in November 2015 with human papillomavirus (HPV)16-positive squamous cell carcinoma of the oropharynx (base of tongue), staged cT2N2bM0. Following induction chemotherapy with docetaxel, cisplatin, and 5-fluorouracil, and concurrent chemoradiotherapy with cisplatin, persistent disease was confirmed by biopsy. In December 2016, she underwent extensive surgery that included partial pharyngectomy with tracheostomy + hemiglossectomy + bilateral neck dissection + microvascular free flap reconstruction with positive margins (ypT4aN2R1). Following surgery with positive margins, complementary systemic therapy was administered (paclitaxel, followed by cetuximab combined with methotrexate). In 2019, the patient presented with locoregional cutaneous recurrence, which required hemostatic palliative radiotherapy. Nivolumab was initiated in December 2019, and a CR was achieved about two months later, by February 2020. Treatment was discontinued in February 2021 due to immune-related toxicity (bullous pemphigoid, Common Terminology Criteria for Adverse Events v5.0, grade 3). Remarkably, the patient has maintained a CR for more than four years after discontinuation of immunotherapy, as confirmed by imaging in 2025. This case highlights the potential for durable CRs after immunotherapy discontinuation in heavily pretreated HPV-positive HNSCC, raising important questions regarding optimal treatment duration, patient selection, and the role of immune-related adverse events as a potential marker of response.

Open article ↗

2026-05-28 | Phase 2 study of intratumoral oncolytic VV1 plus cemiplimab: Simon's stage 1 results from head and neck squamous cell carcinoma (HNSCC) cohort.

e18026 Background: Immune checkpoint inhibitor (ICI) therapy is part of standard of care first-line therapy for recurrent or metastatic (R/M) HNSCC. However, less than 20% of patients (CPS ≥1) have an objective response to ICI monotherapy, and most tumors progress within ~3 months. We sought to improve the proportion of patients who benefit from a chemotherapy-free regimen by combining intratumoral (IT) VV1 oncolytic virus (VSV-IFNβ-NIS) injections with the anti-PD-1 antibody, cemiplimab. We report a pre-planned analysis of Simon's stage 1 results. Methods: We activated a phase 2 study testing the efficacy of first line IT VV1 plus cemiplimab in 1 st line patients with R/M HNSCC. A Simon's two-stage design was employed whereby 10 patients would be accrued in stage 1, and if 3 or more responses were observed, 12 additional patients would be accrued for stage 2. The primary endpoint was objective response rate (ORR) per investigator (RECIST 1.1). Eligible patients had untreated R/M HNSCC from primary oropharynx, oral cavity, hypopharynx, or larynx sites with CPS ≥1. Patients had to have at least one measurable lesion amenable to IT injection. Treatment comprised of IT injections to 1-5 lesions of oncolytic VV-1 virus and IV cemiplimab 350 mg on day 1, repeated every 21 days. Each lesion could be injected 3 times; a 4th injection was allowed if a partial response (PR) was achieved after 3 injections. Cemiplimab could be continued for up to 2 years until progression or unacceptable toxicity. Results: Patient and tumor characteristics, as well as efficacy and toxicity are summarized in the table below. Ten patients were treated at the time of Stage 1 analysis, with 3 showing a confirmed PR for ORR of 30%. Responder CPS scores were 45, 12 and 20%. Two of the responders subsequently showed progression after 6.2 and 9.9 months, the third has maintained PR at 7.7 months to date. Eight of 10 patients showed decrease in the sum of target lesion size (mean decrease of 16%; range -57 to 77%). One grade 2 event of ICI nephritis resolved with corticosteroid treatment. Conclusions: Three patients showed confirmed PR by RECIST 1.1 in Simon's stage 1, meeting criteria to proceed to Simon's stage 2. A total of 22 patients in the HNSCC will be enrolled. VV1 plus cemiplimab shows promise in first line R/M HNSCC based on these initial results. Clinical trial information: NCT04291105 . Patient demographics. N (treated) 10 Sex 20% female Median age (y) 60 (54 – 76) Oropharynx 7 HPV+ 7 Oral cavity 3 PD-L1 CPS median (range) 7.5 (1-45%) Locoregional injection 3 Distant injection 6 Local and distant injection 1 Best response (RECIST 1.1) PR 3 SD 5 PD 2 Adverse Events #pts any VV1/cemiplimab-related G3 AE 4 Lymphopenia 3 Elevated ALK 1

Open article ↗

2026-05-28 | Real world efficacy of cetuximab plus chemotherapy as first-line treatment of recurrent and/or metastatic head and neck squamous cell carcinoma.

e18032 Background: Head and neck squamous cell carcinoma (HNSCC) represent a major therapeutic challenge due to its biological heterogeneity and variable prognosis. The use of cetuximab combinations plus chemotherapy has been shown to improve survival outcomes. This study aimed to evaluate the clinical characteristics and the impact of cetuximab-based therapy on overall survival (OS) and progression-free survival (PFS) in patients with recurrent and/or metastatic (R/M) HNSCC. Methods: A retrospective study was conducted including patients diagnosed with R/M HNSCC and treated at the Instituto Nacional de Enfermedades Neoplásicas (INEN) between 2020 and 2024. Clinical variables, response rates, OS, and PFS were analyzed. Survival outcomes were estimated using Kaplan–Meier curves. For survival analysis, patients should receive at least three cycles of cetuximab in combination with chemotherapy. Results: Fifty patients were included, with a median age of 56 years (34% aged >60 years), 54% male, 39% with primary tumors in the oral cavity, and 32% in the oropharynx (19.6% IHC p16-positive). Moderately differentiated carcinoma was the most frequent histology (83.3%). Most patients (80%) had ECOG performance status 1; 34% had a BMI <18, and 78% presented a prognostic nutritional index (PNI) >45. At the start of cetuximab therapy, 38% had systemic disease (14% with concomitant locoregional recurrence), with the lung being the most common metastatic site (94.7%). 80% of patients had received prior treatment: 32.5% radiotherapy alone, 22.5% surgery plus adjuvant radiotherapy, 17.5% surgery plus adjuvant chemoradiotherapy, 17.5% induction chemotherapy followed by radiotherapy alone, 5% induction chemotherapy followed by concurrent chemoradiotherapy, and 5% definitive concurrent chemoradiotherapy. For R/M disease, the most common regimen was cetuximab plus carboplatin and taxanes (60%), followed by the TEPEx regimen (22%). 74% of patients received at least three cycles of chemotherapy. The objective response rate (ORR) was 32.4% (CR = 5.4%, PR = 27%), and the clinical benefit rate (CR + PR + SD) was 70.2%. Maintenance therapy was administered to 51.4% of patients. The median PFS was 6.87 months (5.99-7.74), median OS since initiation of cetuximab was 9.87 months (5.62-14.12), and median OS since initial diagnosis was 22.1 months (19.17-25.03). Conclusions: Cetuximab-based chemotherapy provided meaningful clinical benefit in patients with recurrent and/or metastatic HNSCC, with survival outcomes comparable to those reported in real-world settings. These findings support the continued use of cetuximab in combination regimens as an effective therapeutic option.

Open article ↗

2026-05-27 | Neoadjuvant ivonescimab (AK112, a PD-1/VEGF bispecific antibody) combined with nab-paclitaxel and cisplatin (AP) for resectable locally advanced head and neck squamous cell carcinoma (LA-HNSCC): An exploratory phase II study.

6014 Background: Previously, neoadjuvant PD-1 plus AP followed by surgery and radiotherapy showed promising disease control and laryngeal preservation in resectable LA-HNSCC. Ivonescimab, a PD-1/VEGF bispecific antibody, potentially exerts synergistic anti-tumor activity by normalizing tumor vasculature and enhancing immune infiltration. This study evaluates the efficacy and safety of neoadjuvant Ivonescimab plus AP in resectable LA-HNSCC. Methods: This single-center phase II trial enrolled patients (18-70 yrs) with resectable stage III-IVa LA-HNSCC (oral cavity, oropharynx, hypopharynx, or larynx). Neoadjuvant therapy: 3 cycles of Ivonescimab (20mg/kg Q3W) plus AP, followed by surgery. Postoperative treatment included radiotherapy ± chemotherapy and maintenance Ivonescimab (10mg/kg Q3W) for 14 cycles. Primary endpoints: pCR and 2-year EFS. MRD and PD-L1 CPS were also investigated. Results: By November 2025, 36 patients were enrolled (median age 58; 75% Stage IV). Primary tumor sites were hypopharynx (50.0%), larynx (25.0%) and oral cavity (19.4%). Radiological assessment performed prior to Cycle 3 demonstrated an exceptional objective response rate (ORR) of 100% among 34 evaluable patients. Notably, a remarkably deep radiological response was achieved, with a complete response (CR) rate of 50.0% (17/34) and a partial response (PR) rate of 50.0% (17/34). Deep tumor shrinkage was observed in all cases. 30 patients underwent surgery with a 100% R0 resection rate. The overall pCR rate was 50.0% (15/30). Specifically, pCR was achieved in 70.0% (21/30) of primary lesions and 64.3% (18/28) of lymph nodes. While robust pathological responses were observed in the hypopharynx (64.3%), tongue (57.1%), and oropharynx (50.0%), the pCR rate in the larynx was markedly lower at 12.5%. Crucially, the profound tumor downsizing induced by Ivonescimab enabled volume-reduced resections, achieving 100% successful laryngeal and pharyngeal preservation while maintaining negative margins. High PD-L1 predicted efficacy; median CPS was 30.0 in pCR vs. 10.0 in non-pCR (p=0.18). Notably, 100% of pts with CPS > 30 achieved pCR. Pre-op MRD specificity for pathological conversion was 91.7% (sensitivity 37.5%). Safety: The most common Grade≥3 AEs were pharyngeal fistula (surgical-related) and transient transaminase elevation. Most drug-related AEs were manageable and consistent with the known profiles of PD-1 and VEGF inhibitors. Conclusions: Neoadjuvant Ivonescimab plus chemotherapy demonstrated unprecedented radiological response depth and pathological remission rates in LA-HNSCC. This novel PD-1/VEGF-based dual blockade may redefine neoadjuvant standards for head and neck cancer. High CPS and MRD negativity are robust predictors of deep pathological response. Clinical trial information: NCT06537011 .

Open article ↗

2026-05-27 | Outcomes of PD-(L)1 inhibitor continuation or rechallenge after first-line progression in recurrent or metastatic head and neck squamous cell carcinoma.

6059 Background: PD-(L)1 inhibitors are a standard first-line (1L) backbone for recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC). However, many patients progress after 1L PD-(L)1–based therapy, and optimal post-progression strategies remain undefined. In particular, the benefit of continuing or rechallenging PD-(L)1 inhibitors beyond progression is unclear. Methods: In this multicenter retrospective study, we included patients diagnosed with R/M HNSCC (oral cavity, oropharynx, larynx, and hypopharynx) between 2016 and May 2025 at Samsung Medical Center and Mass General Brigham. Eligible patients received 1L PD-(L)1–containing regimen, experienced disease progression, and underwent subsequent second-line systemic therapy. Patients were categorized by post-progression strategy: continuation or rechallenge with PD-(L)1 inhibitors versus non–PD-(L)1–based therapy. Overall survival (OS) was defined as the time from initiation of 1L therapy to death from any cause. Results: A total of 252 patients with R/M HNSCC met eligibility criteria. Median age was 64; 191 (76%) were male; 68 (27.0%) were HPV-positive; and 217 (86%) were PD-L1 positive (CPS ≥1). Twenty-six patients (10.3%) received anti-PD-(L)1 monotherapy, and 84 (33%) remained on 1L therapy for ≥6 months. Median OS for the entire cohort was 18 months (95% CI, 15.9-20.1). Median OS was 21.1 months among patients who continued or were rechallenged with PD-(L)1 inhibitor (n = 112) versus 14.4 months in those who were not (n = 140) (p < 0.001). On multivariable analysis including post-progression PD-(L)1 continuation/rechallenge, HPV status, PD-L1 expression, age, sex, ECOG performance status, and duration of 1L PD-(L)1 therapy, continuation or rechallenge with PD-(L)1 inhibitors (HR 0.583, p=0.003) and 1L PD-(L)1 duration ≥6 months (HR 0.487, p<0.001) were independently associated with improved OS. Conclusions: In this study, continuation or rechallenge with PD-(L)1 inhibitors after progression on 1L therapy was associated with improved OS in patients with R/M HNSCC, independent of PD-L1 expression or HPV status. Prolonged benefit from 1L PD-(L)1 therapy was also independently associated with favorable survival. These findings suggest that selected patients may derive continued clinical benefit from anti-PD-(L)1–based strategies beyond progression and support prospective studies to refine patient selection and optimize post-progression treatment strategies.

Open article ↗

proteins

2026-05-28 | Empegfilgrastim for primary febrile neutropenia prophylaxis during induction chemotherapy with docetaxel, cisplatin, and 5-fluorouracil in head and neck squamous cell carcinoma.

e18030 Background: Induction chemotherapy (CT) with docetaxel, cisplatin, and 5fluorouracil (DCF) before chemoradiotherapy can improve disease control in advanced head and neck squamous cell carcinoma (HNSCC) but is associated with a high risk of severe hematologic toxicity, including febrile neutropenia (FN). Empegfilgrastim is a long-acting granulocyte colony stimulating factor (GCSF) designed to reduce chemotherapy-induced neutropenia and FN. This single-center retrospective study evaluated the incidence of neutropenic complications in HNSCC patients (pts) receiving DCF induction CT with primary FN prophylaxis using empegfilgrastim. Methods: This was a retrospective, single-center cohort of pts with unresectable stage III/IVA hypopharyngeal, laryngeal, or oropharyngeal squamous cell carcinoma treated with 3 cycles of DCF induction CT (docetaxel 75 mg/m² day 1, cisplatin 75 mg/m² day 1, 5fluorouracil 1000 mg/m²/day as a continuous infusion on days 1–4, every 3 weeks), followed by empegfilgrastim 7.5 mg subcutaneously on days 4–8 of each cycle. The primary endpoint was the incidence of grade 3–4 neutropenia (CTCAE v5.0). Secondary endpoints included incidence of FN, nonhematologic adverse events (AEs) grade ≥3, and tumor response after induction CT. Results: A total of 55 pts with unresectable stage III/IVA HNSCC were included: hypopharynx (n=33), larynx (n=8), and oropharynx (n=14). The median age was 60 years (range 39–77); 83% had ECOG performance status 0–1 and 85% were male. Most pts (48/55, 89%) completed all 3 planned DCF cycles. Objective response was assessable in 32 pts, of whom 70% achieved an objective response, including 13 complete responses; the median change in target lesion size was −60% (range −84% to −28%). Grade 3–4 neutropenia occurred in 6 pts (11%), and FN in 4 pts (7.3%). The incidence of any nonhematologic AE grade ≥3 was 3/55 (5%). Conclusions: Primary prophylaxis with empegfilgrastim during DCF induction CT was associated with a relatively low incidence of grade 3–4 neutropenia and FN in pts with advanced HNSCC, while allowing the majority to complete planned treatment. Further analyses are planned to compare the efficacy and safety of empegfilgrastim administration on day 2 versus day 3 of the DCF regimen.

Open article ↗

2025-09-30 | Clinical and morphogenetic classification of squamous cell carcinoma of the oral cavity and oropharynx

Squamous cell carcinoma of the head and neck (SCCHN) is a biologically heterogeneous disease in which the anatomical location and stage of the disease do not always correlate with the actual prognostic and clinical behavior of the tumor. The results of translational studies, including TCGA and high-throughput transcriptome analysis, demonstrate differences between the mechanisms of carcinogenesis associated with HPV infection and TP53 gene mutations. In the present study, a clinically applicable surrogate classification of HPV-related squamous cell carcinoma was developed based on immunohistochemical expression of p16, p53, and PD-L1 proteins, with eight molecular subtypes identified that reflect key genetic events and features of the immune microenvironment. Each subtype is characterized by unique clinical and morphological features, as well as significantly distinct overall and recurrence-free survival rates. The proposed classification allows patients to be stratified into prognostic risk groups and serves as a basis for personalized therapy selection, including chemoradiotherapy, immunotherapy, modification of adjuvant treatment strategies, and minimally invasive surgical approaches. Thus, immunohistochemical identification of surrogate subtypes of SCCHN is an accessible and clinically significant tool for optimizing cancer care and predicting disease outcomes. Плоскоклеточный рак головы и шеи (ПРГШ) представляет собой биологически гетерогенное заболевание, в рамках которого анатомическая локализация и стадия опухолевого процесса не всегда отражают истинное прогностическое и клиническое поведение опухоли. Результаты трансляционных исследований, включая TCGA и высокопроизводительный транскриптомный анализ, демонстрируют различия в механизмах канцерогенеза, связанных с ВПЧ-инфекцией и мутациями гена TP53. В представленном исследовании разработана клинически применимая суррогатная классификация ПРГШ, основанная на иммуногистохимической экспрессии белков p16, p53 и PD-L1, с выделением восьми молекулярных подтипов, отражающих ключевые генетические события и особенности иммунного микроокружения. Каждый из подтипов характеризуется уникальными клинико-морфологическими признаками, а также достоверными различиями в общей и безрецидивной выживаемости. Предложенная классификация позволяет стратифицировать пациентов по прогностическим группам риска и служит основанием для персонализированного подбора терапии, включая химиолучевое лечение, иммунотерапию, модификацию адъювантной тактики и минимально инвазивные хирургические подходы. Таким образом, иммуногистохимическая идентификация суррогатных подтипов ПРГШ представляет собой доступный и клинически значимый инструмент для оптимизации онкологической помощи и прогнозирования исходов заболевания.

Open article ↗

2025-04-21 | Abstract 6928: Combination treatment with cisplatin and PG3 for p53-mutated head & neck cancers

Abstract More than 90% of head & neck (H&N) cancers are squamous cell carcinoma (HNSCC) that occur from the mucosal epithelial tissue of the oral cavity, oropharynx, and larynx. About 30∼40% of stage I or II HNC patients are curable and show improved survival rates after surgery or radiotherapy alone. However, over 60% of stage III or IV HNC patients require chemotherapy. Cisplatin is one of standard chemotherapy drugs for stage III and IV patients. In addition, the mutation frequency of the p53 gene in HNSCC is 65-85%. DNA damage following cisplatin treatment can activate apoptosis via p53 in p53 wild-type cancer cells. In p53-mutated/deleted cancer cells, DNA-damage drugs can lead to cell death through other mechanisms, such as integrated stress response (ISR). There multiple cisplatin-resistance mechanisms were reported. Nucleotide excision repair (NER) is known as the primary strategy for repair of cisplatin-induced DNA damage. Elevated ERCC1 and ERCC5 expression enhance NER and are associated with cisplatin resistance in HNSCC patients. It was reported that ATF4 downregulation promoted cisplatin resistance in p53 mutated and deleted gastric cancers. A small molecule PG3 treatment triggers ISR and leads to cell apoptosis through HRI/eIF2α/ATF4/PUMA pathway in p53-mutated and deleted colorectal cancer cell lines. We hypothesize that (1) combination treatment of PG3 with cisplatin can reduce side effects of cisplatin through reducing the dose of cisplatin, which can be achieved by enhanced induction of integrated stress response, (2) PG3 can sensitize cisplatin-resistant and p53-mutated H&N cancer cells to cisplatin through enhanced induction of integrated stress response. The combination treatment shows synergistic effects in p53-mutated FaDu and Cal27 H&N cancer cells. In combination therapy, use of PG3 allows use of a lower cisplatin dose to achieve a therapeutic benefit. The combined treatment enhances ISR induction, and the ISR contributes to cell apoptosis. We identified that cisplatin or the combination treatment activates the HRI/ATF4/NOXA pathway. NOXA mediates Mcl-1 degradation and is responsible for the combination treatment-induced apoptosis. Citation Format: Xiaobing Tian, Wafik S. El-Deiry. Combination treatment with cisplatin and PG3 for p53-mutated head & neck cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6928.

Open article ↗

2023-03-31 | Data from DNA Repair Biomarker Profiling of Head and Neck Cancer: Ku80 Expression Predicts Locoregional Failure and Death following Radiotherapy

<div>Abstract<p><b>Purpose:</b> Radiotherapy plays an integral role in the treatment of head and neck squamous cell carcinoma (HNSCC). Although proteins involved in DNA repair may predict HNSCC response to radiotherapy, none has been validated in this context. We examined whether differential expression of double-strand DNA break (DSB) repair proteins in HNSCC, the chief mediators of DNA repair following irradiation, predict for treatment outcomes.</p><p><b>Experimental Design:</b> Archival HNSCC tumor specimens (<i>n</i> = 89) were assembled onto a tissue microarray and stained with antibodies raised against 38 biomarkers. The biomarker set was enriched for proteins involved in DSB repair, in addition to established mechanistic markers of radioresistance. Staining was correlated with treatment response and survival alongside established clinical and pathologic covariates. Results were validated in an independent intramural cohort (<i>n</i> = 34).</p><p><b>Results:</b> Ku80, a key mediator of DSB repair, correlated most closely with clinical outcomes. Ku80 was overexpressed in half of all tumors, and its expression was independent of all other covariates examined. Ku80 overexpression was an independent predictor for both locoregional failure and mortality following radiotherapy (<i>P</i> < 0.01). The predictive power of Ku80 overexpression was confined largely to HPV-negative HNSCC, where it conferred a nine-fold greater risk of death at two years.</p><p><b>Conclusions:</b> Ku80 overexpression is a common feature of HNSCC, and is a candidate DNA repair-related biomarker for radiation treatment failure and death, particularly in patients with high-risk HPV-negative disease. It is a promising, mechanistically rational biomarker to select individual HPV-negative HNSCC patients for strategies to intensify treatment. <i>Clin Cancer Res; 17(7); 2035–43. ©2011 AACR</i>.</p></div>

Open article ↗

2018-10-16 | Effectiveness of Oxytocin on Reducing Alcohol Consumption and Depression Syndrome in a Patient with Oropharyngeal Carcinoma

Introduction: Stopping or controlling alcohol consumption in alcohol-related cancers can increase survival rates. Oxytocin due to its potential in craving modulation has been suggested as an alternative therapy. Case Presentation: The patient was alcohol-abused 67-year-old male with a diagnosis of metastatic oropharyngeal squamous cell carcinoma and dysthymia syndrome, which was selected using a respondent-driven sampling (RDS) method. The patient was treated with intranasal oxytocin in two stages and for 6 weeks, and in the control phase, placebo was used. Alcohol consumption rate, its related problems, and changes in the depression index were considered as the primary outcome. The association of mood with alcohol consumption was considered as the secondary outcome. The data were analyzed, using the generalized estimation equation (GEE), a generalized linear mixed models (random effect model) with repeated measures, and repeated measures correlation. Primary outcomes showed that intranasal oxytocin caused a significant decrease in alcohol consumption and its problems related to mood. However, this reduction did not remain until the follow-up stage. Secondary outcomes showed that there is a direct relationship between the dysthymia index and alcohol consumption. Conclusions: The reduction of neurotic cue reactivity induced by the oxytocin function can, with the improvement of the mood, stop the cycle of craving and consumption. However, this hypothesis requires controlled clinical trials.

Open article ↗

other

2025-12-29 | Oropharyngeal Helicobacter pylori colonization increases risk and worsens prognosis of head and neck squamous cell carcinoma

Helicobacter pylori (H. pylori) colonization in the oropharynx has been suggested to contribute to the development of head and neck squamous cell carcinoma (HNSCC), but prospective evidence remains limited. This prospective cohort study aimed to investigate the association between oropharyngeal H. pylori colonization, including its virulence gene types, and the risk and prognosis of HNSCC. A total of 220 high-risk individuals and 220 diagnosed HNSCC patients were enrolled. Oropharyngeal samples were collected for H. pylori detection by culture and quantitative PCR (qPCR). Virulence genes cagA and vacA were genotyped. Cox proportional hazards models assessed HNSCC incidence and overall survival, with Kaplan–Meier and log-rank tests evaluating survival differences. H. pylori positivity was significantly higher in the HNSCC group compared to the high-risk group (43.6% vs. 32.7%, P = 0.033). In high-risk individuals, H. pylori colonization was an independent risk factor for HNSCC onset (HR = 1.50, 95% CI: 1.02–2.21, P = 0.039), with higher bacterial loads and presence of high-virulence genotypes (e.g., cagA+/vacA s1/m1) linked to increased risk (P < 0.05). Among HNSCC patients, H. pylori-positive individuals showed higher recurrence (26.0% vs. 16.9%, P = 0.018) and mortality rates (13.5% vs. 8.1%, P = 0.043), with poorer overall survival (HR = 1.57, P = 0.035). Co-infection with HPV may further complicate the clinical profile, potentially involving the local immune microenvironment. Oropharyngeal H. pylori colonization, particularly by high-virulence strains, significantly elevates the risk of HNSCC development and worsens clinical outcomes. The interplay between H. pylori and HPV suggests the need for integrated pathogen screening and targeted interventions to improve early detection and individualized treatment strategies for HNSCC.

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 ↗

2023-09-13 | PD-L1 and p53 expression in squamous cell carcinoma of the oropharynx depending on human papilloma virus status

Introduction. High-risk human papilloma virus (Hpv), especially genotype 16, causes oropharyngeal squamous cell carcinoma (OSCC). It is detected in about 70 % of tumors developing from lymphoid tissue of the tonsils or the base of the tongue. Due to the increased number of Hpv-positive OSCC, Hpv status is considered a marker of OSCC clinical outcome. Easy testing, low cost, reliability, and high sensitivity of immunohistochemical analysis for p16INk4a allowed to widely use this method for Hpv status determination. Aim. To determine the association between programmed death-ligand 1 (pD-L1) and p53 expression and presence of indirect Hpv marker – p16INk4a – in patients with OSCC. Materials and methods . The study included 76 patients with OSCC т1–4N0–3m0 who received treatment at the Republican Specialized Scientific and practical medical Center of Oncology and Radiology (n = 37) and its Tashkent branch (n = 39) between 2015 and 2020. for all selected patients, retrospective immunohistochemical analysis for the presence of p16INk4a, pD-L1 and р53 in tumor samples fixed with formalin in paraffin blocks was performed. In our work, immunohistochemical examination for p16INk4a was the only relevant tool for Hpv status determination. To reinforce its prognostic significance, we used additional molecular markers pD-L1 and p53 which play an important role in carcinogenic transformation and OSCC progression. Results. The results of immunohistochemical analysis showed that p16INk4a overexpression was accompanied by positive pD-L1 reaction in 46 % (6/13) of cases; there were no cases of positive expression of mutant type p53. wild type p53 was identified in only 1 (3 %) case in combination with p16INk4a overexpression. Conclusion. The developed panel consisting of 3 molecular markers (p16INk4a, pD-L1 and р53) may open new horizons in accurate prognosis, risk stratification and understanding of OSCC molecular signature. This, in turn, will help clinicians in selection of individual therapy strategies for treatment de-escalation and outcome optimization.

Open article ↗

2018-07-27 | Mucosal HPV E6/E7 Peptide Vaccination in Combination with Immune Checkpoint Modulation Induces Regression of HPV+ Oral Cancers

Abstract High-risk human papillomavirus (HPV)–associated squamous cell carcinomas of the oropharynx (SCCOP) are among the fastest growing cancers. After standard-of-care treatment, however, patients with HPV+ SCCOP have better overall and disease-specific survival than patients with HPV− SCCOP, suggesting the importance of HPV-specific immunity. We reasoned that therapeutic vaccination targeting the HPV-16 E6 and E7 oncogenes could elicit high-affinity, high-frequency tumor antigen–specific T-cell responses, which could then be augmented and shielded from suppression in the tumor microenvironment by immune checkpoint modulation. In this study, we used a preclinical syngeneic mouse model of oral cancer comprised of mouse tonsil-derived epithelial cells stably expressing HPV-16 E6 and E7 genes along with H-ras oncogene (mEER) to identify combinations of vaccination and checkpoint antibodies capable of promoting tumor regression. Intranasal HPV E6/E7 peptide vaccination and single checkpoint antibodies failed to elicit responses in more than half of animals; however, 4-1BB agonist antibody along with either CD40 agonist antibody or CTLA-4 blockade eliminated the majority of established mEER tumors. The combination of intranasal HPV peptide vaccine and α4-1BB and αCTLA-4 antibodies produced curative efficacy and a better safety profile against orally implanted mEER tumors. Correlates of protective immunity included enhanced intratumoral levels of CD8 T cells relative to immunosuppressive regulatory T cells and myeloid-derived suppressor cells. Overall, our results demonstrate combination vaccine-immunotherapy modalities as novel treatment options for HPV+ SCCOP. Significance: Combinations of vaccine and checkpoint modulation are effective and safe treatment options for HPV+ oral cancers. Cancer Res; 78(18); 5327–39. ©2018 AACR.

Open article ↗

2008-06-01 | Down-regulation of Mcl-1 with antisense technology alters the effect of various cytotoxic agents used in treatment of squamous cell carcinoma of the head and neck

Antisense oligonucleotides have recently been identified as new anticancer agents. Since human head and neck cancer cells highly express the antiapoptotic protein myeloid cell leukemia-1 (Mcl-1), the aim of this study was to explore the efficacy of the Mcl-1 suppression in combination with various cytotoxic agents in the head and neck cancer cell line SCC9. After oligonucleotide transfection and/or treatment with cisplatin, 5-fluorouracil (5-FU), gemcitabine, paclitaxel or cetuximab, proliferation assays were performed to determine cell viability. The expression patterns of Mcl-1, Bax and Bak were assessed by Western blot analysis and the apoptotic cells were determined by immunohistochemistry using the M30 antibody. A combined Mcl-1 antisense oligonucleotide treatment with paclitaxel, cetuximab and gemcitabine led to a significant reduction in the viable cells. However, the combination with cisplatin and 5-FU showed only moderate synergistic cytotoxic effects. According to the cytotoxic data, distinct apoptosis rates were observed after the combined treatment with the different substances. Western blot analysis also showed a significant suppression of the Mcl-1 synthesis. Our data show that the Mcl-1 antisense oligonucleotide in combination with certain cytotoxic agents has the potential to significantly decrease cell viability in vitro.

Open article ↗