EGFR/HER2 Dual-Target CAR-NK Cells for Recurrent or Metastatic HNSCC

• Adults with recurrent or metastatic HNSCC that is not amenable to curative surgery or radiotherapy will undergo central biomarker assessment using archival and/or fresh tumor tissue. Mandatory enrollment biomarkers for this example are EGFR and HER2/ERBB2. CD70 expression will be collected as an exploratory biomarker and may guide future cohort amendments.
• Eligible participants will receive lymphodepleting fludarabine and cyclophosphamide on Days -5 to -3, followed by infusion of allogeneic EGFR/HER2 dual-target CAR-NK cells on Days 0, 7, and 14. The investigational product in this example is assumed to include membrane-bound IL-15 to support persistence and an inducible caspase-9 safety switch for controllability.
• Part A uses a modified 3+3 dose-escalation design to identify the maximum tolerated dose , dose-limiting toxicities (DLTs), and the RP2D / recommended schedule. Part B is a biomarker-enriched expansion cohort treated at the RP2D to estimate objective response rate and durability of disease control.
• An optional second cycle after Day 28 may be permitted for participants with stable disease or objective response and without prohibitive toxicity. Serial blood, ctDNA, immune profiling, and optional on-treatment biopsy samples will be collected to study CAR-NK expansion, persistence, antigen modulation, and resistance pathways.

Inclusion criteria

• Age 18 to 75 years at the time of consent.
• Histologically or cytologically confirmed squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx that is recurrent or metastatic and not amenable to curative surgery or radiotherapy.
• Tumor meets protocol-defined central biomarker criteria for both EGFR and HER2 / ERBB2. Suggested example thresholds: EGFR membranous IHC 2+ / 3+ in at least 50% of viable tumor cells and HER2 IHC 2+ / 3+ in at least 10% of viable tumor cells and / or protocol-defined genomic amplification / activating alteration.
• Disease progression on or after at least one prior systemic regimen for recurrent / metastatic disease, including platinum therapy and PD-1 / PD-L1 inhibitor unless contraindicated or not appropriate. Prior cetuximab is allowed.
• At least one measurable lesion by RECIST 1.1.
• ECOG performance status 0 to 1.
• Adequate marrow, renal, hepatic, cardiac, and pulmonary function per protocol-defined laboratory thresholds.
• Life expectancy of at least 12 weeks.
• Availability of archival tissue or willingness to provide fresh tumor tissue for central biomarker testing; willingness to undergo serial blood sampling and optional research biopsy if medically feasible.
• Negative pregnancy test for participants of childbearing potential and agreement to use highly effective contraception during protocol-defined treatment and follow-up windows.
• Ability to understand and sign informed consent.

Exclusion criteria

• Nasopharyngeal carcinoma, salivary gland malignancy, cutaneous squamous cell carcinoma, non-squamous histology, or carcinoma of unknown primary.
• Untreated, unstable, or symptomatic central nervous system metastases or leptomeningeal disease.
• Prior gene-modified adoptive cell therapy (for example CAR-T, CAR-NK, or TCR-T) within a protocol-defined washout period, or prior allogeneic stem-cell transplant with active graft-versus-host disease.
• Active uncontrolled infection, including uncontrolled bacterial, fungal, or viral infection; active hepatitis B or C with detectable viral load; or uncontrolled HIV infection.
• Active autoimmune disease requiring systemic immunosuppression, or chronic corticosteroid use above the protocoldefined threshold before lymphodepletion.
• Clinically significant interstitial lung disease, oxygen dependence, or another serious pulmonary condition that would materially increase cell-therapy risk.
• Clinically significant cardiovascular disease including recent myocardial infarction, unstable angina, uncontrolled arrhythmia, uncontrolled hypertension, or symptomatic heart failure.
• Major surgery within 28 days before lymphodepletion, or anticancer therapy / investigational therapy within the protocol-defined washout window.
• Pregnancy or breastfeeding.
• Known severe hypersensitivity to fludarabine, cyclophosphamide, or cell-product excipients.
• Any medical, psychiatric, or social condition that, in the investigator's judgment, would compromise safety, protocol compliance, or informed consent.