This illustrative Phase 1/Phase 2 study tests allogeneic dual-target GD2/B7-H3 (CD276) CAR-NK cells in children and young adults with relapsed or refractory neuroblastoma. After lymphodepletion, participants receive IV CAR-NK cells;Part A defines the RP2D and Part B estimates preliminary activity

The investigational product in this example is a cord blood-derived allogeneic NK-cell therapy engineered to express a dual-target CAR recognizing GD2 and B7-H3, supported by IL-15 to improve short-term persistence and equipped with an inducible safety switch. The study is designed as a multicenter Phase 1/Phase 2 protocol: Part A uses a standard 3+3 dose-escalation approach across predefined dose levels, and Part B expands at the RP2D in a biomarker-characterized population. All participants undergo central review of tumor tissue or marrow for GD2 and B7-H3 expression before treatment. Patients receive protocol-defined lymphodepletion followed by CAR-NK infusion on Day 0, with optional additional infusions on Days 7 and 14 if there is no dose-limiting toxicity (DLT), uncontrolled cytokine release syndrome (CRS), or rapid progression. Formal disease assessment uses revised International Neuroblastoma Response Criteria (rINRC). Correlative studies assess CAR-NK expansion and persistence, cytokine kinetics, tumor-response associations with antigen density, and whether future development should remain dualtarget or shift toward a GD2-dominant or B7-H3-enriched strategy. Long-term follow-up for gene-modified cellular therapy is planned per local regulatory requirements.

Inclusion Criteria:

• Age 12 months to 21 years at consent/assent.
• Histologically confirmed neuroblastoma or ganglioneuroblastoma with relapsed, refractory, progressive, or persistent high-risk disease for which no curative standard option is available.
• Measurable or evaluable disease according to revised International Neuroblastoma Response Criteria (rINRC), including MIBG-avid disease, CT/MRI-evaluable soft-tissue disease, and/or bone marrow disease.
• Tumor material available for central assessment of GD2 and B7-H3 expression; at least one target must be positive.

GD2 is treated as the core target and B7-H3 as the complementary target for correlative target-prioritization analyses.

• Prior exposure to standard neuroblastoma therapy, including anti-GD2-based therapy, unless contraindicated, unavailable, or declined for a documented medical reason.
• Lansky or Karnofsky performance score >= 50.
• Life expectancy >= 8 weeks.
• Recovery from clinically significant acute toxicities of prior therapy and protocol-defined washout from chemotherapy, biologics, radiation, and prior cell therapy.
• Adequate organ function: hematologic, renal, hepatic, cardiac, and pulmonary function considered sufficient by protocoldefined laboratory and clinical thresholds.
• Negative pregnancy test for patients of childbearing potential and agreement to use effective contraception during the protocol-defined period.
• Written informed consent from parent/legal guardian and assent from the participant when appropriate.

Exclusion Criteria:

• Active uncontrolled infection, including bacteremia, uncontrolled viral infection, or invasive fungal disease.
• Pregnancy or breastfeeding.
• Active grade >= 2 graft-versus-host disease, or systemic immunosuppression for treatment/prevention of graft-versushost disease within the protocol-defined washout period after prior allogeneic transplant.
• Symptomatic or unstable central nervous system disease requiring urgent medical intervention.
• Prior genetically modified cellular therapy within the protocol-defined washout window, or unresolved clinically significant toxicity from prior cell therapy.
• Active autoimmune disease requiring systemic immunosuppressive therapy.
• Clinically significant uncontrolled cardiovascular, pulmonary, hepatic, renal, or neurologic disorder that would increase study risk.
• Known hypersensitivity to fludarabine, cyclophosphamide, study-product components, or supportive-care medications required by the protocol.
• Known uncontrolled HIV infection or uncontrolled hepatitis B or C.
• Any medical, psychosocial, or logistical condition that, in the investigator's judgment, would make study participation unsafe or would impair protocol adherence.

Masking is not used because the study is an earlyphase cell-therapy trial focused on safety, dose finding, feasibility, pharmacodynamics, and preliminary efficacy.