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

A Phase 1/2, Open-Label, Biomarker-Enriched Study of Allogeneic EGFR/HER2 Dual-Target CAR-NK Cells Following Fludarabine/Cyclophosphamide Lymphodepletion in Adults With Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma

This example Phase 1/2 protocol evaluates allogeneic EGFR/HER2 dual-target CAR-NK cells in adults with recurrent or metastatic HNSCC whose tumors meet protocol-defined co-expression criteria for EGFR and HER2/ERBB2. The study is designed as a biomarker-enriched, open-label, non-randomized trial with a dose-escalation safety lead-in followed by an expansion cohort at the recommended Phase 2 dose (RP2D).

1. 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.
2. 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.
3. 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.
4. 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.