Immunotherapy is transforming the treatment landscape of head and neck cancer—expanding beyond recurrent and metastatic settings into neoadjuvant, adjuvant, and localized delivery strategies. From intratumoral CAR-T cell infusions to intra-arterial checkpoint blockade and PD-1–based chemo-immunotherapy, new trials are redefining how advanced and resectable disease is approached.
Across leading centers in London, Nanjing, New York, and Shanghai, innovative Phase I–III studies are exploring modalities that target the tumor microenvironment, enhance local immune activation, and minimize systemic toxicity. This growing portfolio includes intratumoral T4 CAR-T therapy, intra-arterial immunotherapy, tislelizumab-based induction regimens, and biomarker-driven combinations with radiation, surgery, or targeted agents—all aiming to achieve durable responses in traditionally immunologically “cold” head and neck cancers.
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T4 Immunotherapy for Recurrent or Locally Advanced Head and Neck Cancer
This Phase I, open-label, non-randomized, dose-escalation trial, conducted in the United Kingdom, investigates the safety and feasibility of T4 immunotherapy—a novel, intratumoral CAR-T cell therapy—for patients with squamous cell carcinoma of the head and neck (SCCHN) who are not candidates for conventional active treatment.
Led by researchers at King’s College London, the study explores a first-in-human approach using autologous T cellsengineered to express a second-generation chimeric antigen receptor (CAR) known as T1E28z, which targets multiple ErbB family receptors (HER1–HER4) overexpressed in epithelial tumors.
Participants receive direct intratumoral injections of the modified T4+ T cells without prior lymphodepletion. A classical 3+3 dose-escalation design is used, increasing from 10⁷ to 10⁹ transduced cells, based on safety monitoring and tolerability. Up to 30 patients are expected to enroll.
- Primary endpoint: safety and dose-limiting toxicity.
- Secondary endpoints: preliminary evidence of antitumor activity, immune activation within the tumor microenvironment, and feasibility of local CAR-T administration.
Eligible patients must have histologically confirmed SCCHN, measurable locoregional disease amenable to intratumoral injection, ECOG performance status 0–2, and adequate organ function. Exclusions include airway obstruction, vascular invasion, active infections (HIV, hepatitis), uncontrolled comorbidities, autoimmune disease, pregnancy, and prior T4 immunotherapy.
This trial represents one of the earliest attempts to deliver regionally administered CAR-T therapy for solid tumors, aiming to achieve potent local immune activation with reduced systemic toxicity. The study builds on preclinical and translational work published by van Schalkwyk et al. (Hum Gene Ther Clin Dev, 2013), establishing the framework for localized CAR-T delivery in head and neck cancer.
Intra-Tumoral and Intra-Arterial Immunotherapy for Advanced Head and Neck Cancer (Phase II/III Trial)
This Phase II/III, randomized, open-label, multicenter study conducted in China investigates the survival benefit and safety of immune checkpoint inhibitors (PD-1, PD-L1, and CTLA-4 inhibitors) administered through intra-tumoral (IT) or intra-arterial (IA) routes versus standard intravenous (IV) infusion in patients with advanced or recurrent head and neck squamous cell carcinoma (HNSCC).
The trial explores whether localized immunotherapy delivery can enhance treatment efficacy by increasing local drug concentration within the tumor microenvironment while minimizing systemic toxicity, leveraging the pharmacologic principle of the “first-pass effect.”
Up to 200 patients with histologically confirmed advanced HNSCC are expected to be enrolled and randomized into three experimental arms:
- Arm 1 (IA Infusion): Targeted delivery of PD-1/PD-L1/CTLA-4 inhibitors or their combinations through neck artery infusion, directly perfusing the tumor-bearing region.
- Arm 2 (IT Injection): Intra-tumoral injection of the same immunotherapeutic agents using interventional techniques for localized immune activation.
- Arm 3 (IV Infusion): Standard peripheral intravenous administration of PD-1/PD-L1/CTLA-4 inhibitors or their combinations, serving as the comparator.
The primary endpoint is overall survival (OS) at two years.
Secondary endpoints include progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse event rate, assessed according to RECIST v1.1 and CTCAE v5.0.
Eligible participants must have measurable disease, ECOG performance status <2, and adequate organ function, with exclusion criteria including uncontrolled comorbidities, active infections, contraindications to neck artery infusion, and pregnancy or lactation.
By directly comparing regional (IA/IT) versus systemic (IV) immunotherapy, this study aims to define whether locally enhanced immune checkpoint blockade can provide superior survival outcomes and improved tolerability for patients with hard-to-treat head and neck cancers.
Tislelizumab Combined With APF Chemotherapy in Locally Advanced Head and Neck Tumors
This Phase II, single-center, open-label study, sponsored by The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School (China), investigates the efficacy, safety, and immune microenvironmental effects of combining tislelizumab (PD-1 inhibitor) with APF chemotherapy—a regimen of albumin-bound paclitaxel, cisplatin, and 5-fluorouracil (5-FU)—in patients with locally advanced head and neck squamous cell carcinoma (HNSCC).
The trial enrolls 29 treatment-naïve patients with histologically or cytologically confirmed tumors of the oral cavity, oropharynx, hypopharynx, or larynx, staged as III–IVb (P16−) or II–III (P16+). All participants have measurable disease per RECIST 1.1 and an ECOG performance status of 0–1.
Participants receive tislelizumab in combination with APF chemotherapy for three 21-day cycles as induction therapy, followed by either:
- Sequential surgery, or
- Radical concurrent chemoradiotherapy (CCRT) for unresectable disease.
The primary endpoint is the pathological complete response (pCR) rate after three cycles of induction therapy, assessed through comparative pathology before and after treatment.
Secondary endpoints include radiographic tumor response (MRI/CT per RECIST v1.1) and safety, evaluated using NCI-CTCAE v4.0. Exploratory analyses will assess gene expression changes within the immune microenvironment to identify biomarkers associated with treatment efficacy.
Eligible patients must have adequate hematologic, renal, and hepatic function, no prior systemic or radiation therapy, and available tumor tissue for molecular studies. Key exclusions include distant metastases, active autoimmune or infectious disease (HIV, HBV, HCV, tuberculosis), major cardiac or hepatic dysfunction, recent major surgery, or pregnancy/lactation.
By integrating tislelizumab-based immunotherapy with multi-agent chemotherapy and locoregional treatment, this study aims to improve pathologic response rates and long-term outcomes in locally advanced HNSCC while advancing understanding of immune-genetic predictors of response to PD-1–based combination therapy.
HNSALV Trial – Combining Immunotherapy, Salvage Surgery, and Intraoperative Radiation Therapy (IORT) for Persistent/Recurrent Head and Neck Cancer
This Phase I, randomized, open-label trial evaluates the safety and feasibility of combining pembrolizumab with salvage surgery and intraoperative radiation therapy (IORT), with or without preoperative external beam radiation therapy (EBRT), in patients with recurrent or persistent head and neck squamous cell carcinoma (HNSCC).
The study enrolls 45 patients with resectable recurrent or persistent HNSCC of the oral cavity, pharynx, or larynx. Participants are randomized to one of three treatment arms:
- Arm A: Pembrolizumab → Salvage surgery → IORT → Pembrolizumab maintenance
- Arm B: Pembrolizumab + low-dose EBRT → Salvage surgery → IORT → Pembrolizumab maintenance
- Arm C: Pembrolizumab + high-dose EBRT → Salvage surgery → IORT → Pembrolizumab maintenance
The primary objective is to evaluate toxicity using NCI CTCAE v4.0.
Secondary endpoints include locoregional control rate (LCR), progression-free survival (PFS), and overall survival (OS).
Correlative studies will explore biomarkers of response (PD-L1, TNF-α, NFκB, TMB) and immune activation (CD8⁺ T cells, Tregs, MDSCs). Quality of life is assessed using EORTC QLQ-C30 and QLQ-HN35.
Immune Biomarker Study for Head and Neck Cancer (ImmunBio-KHT)
This prospective, multi-center, non-interventional study, titled ImmunBio-KHT, aims to define the prognostic and predictive value of intratumoral and systemic immune biomarkers in patients with newly diagnosed, non-metastatic head and neck cancer. Conducted across several academic centers, the study seeks to identify immune-based prognostic signatures that could guide personalized treatment strategies in head and neck oncology.
The trial evaluates immune activity at both the tumor site and in peripheral blood, correlating local and systemic immune processes to develop a composite immune matrix and prognostic score based on tumor immunologic clustering. Ex vivo tumor organoids are also generated for functional biological analyses.
The study cohort includes patients with UICC stage II–IVB squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, paranasal sinuses, or larynx, while the control group consists of non-cancer patients undergoing surgery at participating institutions.
This observational, case-control study uses serial biospecimen collection (blood, saliva, feces, and tumor tissue) before and after surgery and radiotherapy, enabling deep immune profiling through:
- Flow cytometry and immunophenotyping of ~30 immune cell subsets and activation markers (LIPS method, Zhou et al., JITC 2021)
- Cytokine and chemokine profiling via electrochemiluminescent MULTI-ARRAY
- Genetic analyses (whole-exome sequencing, RNASeq, ddPCR) of immune cell transcriptional activity
- Metabolomic and microbiomic profiling of serum, saliva, and stool samples
The primary objective is to define an immune biomarker–based prognostic score, integrating tumor-associated lymphocytes (TAL) and systemic immune parameters. Secondary endpoints include characterization of longitudinal immune changes across treatment, cytokine and metabolite dynamics, and microbiome composition.
Neoadjuvant Cemiplimab With Chemotherapy and Cetuximab in Resectable Head and Neck Cancer
This Phase I, open-label pilot study, led by Memorial Sloan Kettering Cancer Center (MSKCC) in collaboration with Regeneron Pharmaceuticals, evaluates the safety and feasibility of combining cemiplimab (anti–PD-1) with platinum-doublet chemotherapy and cetuximab before surgery in locally advanced, resectable HNSCC.
Up to 40 patients receive:
- Cemiplimab 350 mg every 3 weeks
- Cisplatin or carboplatin + docetaxel/paclitaxel
- Cetuximab weekly for 10 weeks
followed by definitive surgery ± neck dissection.
Postoperative radiation may be omitted if patients achieve major pathologic response with no adverse features.
The primary endpoint is safety, defined by dose-limiting toxicities per NCI CTCAE v5.0.
Secondary objectives include pathologic response and potential omission of adjuvant therapy.
Neoadjuvant Low-Dose Radiotherapy Plus Targeted Immunotherapy vs Targeted Immunotherapy Alone in Resectable HNSCC
This Phase II, open-label randomized trial evaluates whether adding low-dose radiotherapy (LDRT) to targeted immunotherapy enhances antitumor response compared with targeted immunotherapy alone in patients with resectable head and neck squamous cell carcinoma (HNSCC).
The study enrolls patients with operable, locally advanced HNSCC, randomized into two parallel treatment arms:
- Experimental Arm: Tislelizumab (200 mg IV every 3 weeks, days 1 and 22) + Afatinib (30 mg orally daily, days 1–42) combined with low-dose radiotherapy (4 Gy/2 fractions using IMRT) before standard surgery.
- Control Arm: Tislelizumab + Afatinib alone, followed by standard-of-care surgery.
The primary endpoint is major pathologic response (MPR), defined as <10% viable tumor cells at surgery.
Secondary endpoints include pathologic complete response (pCR), objective response rate (ORR), disease-free survival (DFS), progression-free survival (PFS), overall survival (OS), and immune microenvironment remodeling.
This trial builds on prior findings showing that LDRT can safely reprogram the tumor microenvironment and enhance immune activation. By directly comparing LDRT plus immunotherapy versus immunotherapy alone, the study aims to define a synergistic neoadjuvant strategy to improve resectability, immune response, and long-term outcomes in head and neck cancer.
Cetuximab After Immunotherapy for Recurrent or Metastatic HNSCC
This Phase II, open-label, single-arm clinical trial evaluates the efficacy and safety of cetuximab monotherapy in patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) who have failed or become intolerant to prior PD-1–based immunotherapy, either alone or in combination with chemotherapy.
Eligible patients receive cetuximab intravenously once weekly until disease progression or unacceptable toxicity:
- Loading dose: 400 mg/m² IV over 2 hours (Day 1), followed by 1 hour observation.
- Maintenance dose: 250 mg/m² IV weekly (±2 days), infused over 1 hour.
Premedication with diphenhydramine 50 mg IV is administered prior to each infusion.
The primary endpoint is overall response rate (ORR), assessed by RECIST v1.1 criteria.
Secondary endpoints include duration of response (DoR), progression-free survival (PFS), overall survival (OS), and treatment-related toxicities graded by CTCAE v5.0.
Following completion of therapy, patients undergo follow-up at 1 week and every 6–8 weeks thereafter.
Cemiplimab ± Fianlimab in HPV-Positive Head and Neck Cancer With Minimal Residual Disease
This Phase II, randomized, open-label trial investigates whether the combination of cemiplimab (anti–PD-1) and fianlimab (anti–LAG-3) improves recurrence-free survival compared with cemiplimab monotherapy in patients with HPV-positive head and neck squamous cell carcinoma (HNSCC) who have detectable minimal residual disease (MRD) after curative-intent treatment.
Up to 68 adults with histologically confirmed HPV-positive oropharyngeal SCC and detectable circulating tumor HPV DNA (ctHPVDNA) by the NavDx assay will be enrolled. All participants must have completed curative-intent therapy (surgery, radiation, and/or chemotherapy) at least one month prior to enrollment and show no clinical or radiographic evidence of disease.
Participants are randomized to one of two arms:
- Combination Arm: Cemiplimab 350 mg + Fianlimab 1600 mg (fixed-dose combination, IV) administered for 1 year.
- Monotherapy Arm: Cemiplimab 350 mg IV alone for 1 year.
The primary endpoint is recurrence-free survival (RFS) over a follow-up period of up to 5 years.
Secondary objectives include:
- Comparing ctHPVDNA clearance rates between the two regimens.
- Evaluating patterns of recurrence, overall survival (OS), and treatment safety.
This study aims to determine whether dual immune checkpoint blockade (PD-1 + LAG-3) can eliminate minimal residual disease and reduce recurrence risk in HPV-positive HNSCC, potentially establishing a new adjuvant immunotherapy approach for patients with molecular evidence of residual disease following definitive therapy.
Preoperative Immunotherapy in Squamous Cell Carcinoma of the Head and Neck (SCCHN)
This Phase II, multi-arm, open-label study investigates the immunologic and clinical effects of neoadjuvant atezolizumab, alone or in combination with other immune-modulating agents (tiragolumab or tocilizumab), in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) prior to curative surgery and adjuvant therapy.
The trial aims to determine whether short-course preoperative immunotherapy can enhance intratumoral T-cell infiltration, modulate immune pathways, and improve surgical and long-term outcomes.
Participants are enrolled sequentially into the following treatment arms:
- Arm A (Monotherapy): Atezolizumab 840 mg IV every 2 weeks for up to 15 days before surgery.
- Arm A (Adjuvant Subset): The first 9 patients also receive adjuvant atezolizumab 1200 mg IV every 3 weeks for 12 cycles, starting 16 weeks after completion of surgery and radiation/chemoradiation.
- Arm B: Atezolizumab 840 mg IV plus Tiragolumab 600 mg IV on Day 1 of the neoadjuvant period, administered before surgery.
- Arm C: Atezolizumab 840 mg IV plus Tocilizumab 6 mg/kg IV (Tocilizumab infused first, followed 2 hours later by Atezolizumab).
The primary endpoint is the proportion of patients achieving ≥40% increase in intratumoral CD3⁺ T-cell densitybetween pre- and post-treatment biopsies.
Secondary endpoints include R0 resection rate, immune cell profiling (CyTOF, IHC, gene expression), peripheral immune response, safety (CTCAE v5.0), and relapse-free survival (RFS) at 2 years.
Exploratory analyses assess gut microbiome changes, CRP/LDH/IL-6 correlations, and potential development of immune-competent xenograft models.
