This is a first-in-human, open-label, multicenter phase 1/2 study evaluating the safety, feasibility, recommended phase 2 dose (RP2D), and preliminary antitumor activity of allogeneic dual-target CSPG4/GD2 CAR-NK cells (EBDTKN-401) after lymphodepleting chemotherapy in adults with unresectable or metastatic cutaneous melanoma or metastatic uveal melanoma whose disease has progressed after standard therapy

The target-selection review favored CSPG4/GD2 because it gives the strongest melanoma-centered rationale across both cutaneous and uveal disease. EBDTKN-401 is an allogeneic donor-derived NK-cell product engineered with an OR-gate/tandem CAR recognizing CSPG4 or GD2 and an inducible caspase-9 safety switch. Part A uses 3+3 dose escalation to identify the RP2D. Part B evaluates the RP2D in expansion cohorts for cutaneous melanoma and uveal melanoma. Key secondary objectives are objective response, disease control, durability, progression-free survival, overall survival, CAR-NK persistence, and baseline biomarker-response relationships.

Inclusion Criteria:

• Age 18-75 years at consent.
• Histologically confirmed unresectable/metastatic cutaneous melanoma or metastatic uveal melanoma.
• Disease progression after standard therapy, intolerance to standard therapy, or no remaining standard option expected to provide meaningful benefit. For cutaneous melanoma: prior anti-PD-1/L1 (with or without antiCTLA-4) unless contraindicated; if BRAF V600-mutant, prior BRAF/MEK inhibitor therapy or documented unsuitability. For uveal melanoma: prior tebentafusp if HLA-A*02:01-positive and eligible, or documented unsuitability/unavailability plus at least one prior systemic therapy.
• Tumor demonstrates CSPG4 and/or GD2 expression in archival or fresh tissue by central testing (suggested positivity threshold: at least 25% viable tumor cells by IHC or equivalent validated assay).
• At least 1 measurable lesion by RECIST v1.1.
• ECOG performance status 0-1.
• Adequate bone marrow, renal, hepatic, cardiac, and pulmonary function per protocol.
• Life expectancy of at least 12 weeks.
• Treated, stable brain metastases are allowed if neurologically stable for at least 4 weeks and not requiring escalating corticosteroids.
• Willingness to use effective contraception and comply with protocol-required visits, blood sampling, and requested biopsies.

Exclusion Criteria:

• Active symptomatic CNS metastases, leptomeningeal disease, or uncontrolled seizure disorder.
• Prior allogeneic stem cell transplant or solid organ transplant; prior gene-modified cellular therapy within 12 weeks; or anti-cancer therapy too close to lymphodepletion per protocol washout rules.
• Requirement for systemic immunosuppression greater than 10 mg prednisone equivalent/day or uncontrolled autoimmune/inflammatory disease requiring systemic treatment.
• Active uncontrolled infection, including uncontrolled HIV, HBV, or HCV, or fever/sepsis at the time lymphodepletion would begin.
• Clinically significant cardiovascular disease, uncontrolled arrhythmia, recent myocardial infarction, or uncontrolled thromboembolic disease.
• Grade 2 or higher unresolved toxicities from prior therapy, except stable endocrinopathy, alopecia, or vitiligo.
• Pregnancy or breastfeeding.
• Any condition that, in the investigator's judgment, would make lymphodepletion or CAR-NK infusion unsafe.

Open-label conduct is appropriate because cell-product identity, dose level, and near-real-time toxicity management must remain visible to investigators and treating teams in a first-in-human adoptive cell-therapy study.