Ganglioneuroblastoma, High-Risk Neuroblastoma, Refractory Neuroblastoma, Relapsed Neuroblastoma
Conditions
Keywords
pediatric neuroblastoma, CAR-NK, GD2, B7-H3, CD276, dual-targeting, relapsed/refractory, allogeneic, solid tumor immunotherapy, cell therapy, biomarkerinformed design
Brief summary
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
Detailed description
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.
Interventions
BIOLOGICALEB-DTNB-NK
Allogeneic, cord blood-derived NK cells engineered with a dual-target CAR recognizing GD2 and B7-H3 (CD276), with IL-15 support and an inducible safety switch; administered intravenously on Day 0 with optional repeat dosing on Days 7 and 14 if tolerated.
DRUGFludarabine
Lymphodepleting chemotherapy administered before CAR-NK infusion according to the protocol-defined conditioning regimen.
DRUGCyclophosphamide
Lymphodepleting chemotherapy administered before CAR-NK infusion according to the protocol-definedb conditioning regimen.
Sponsors
Beijing Biotech
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Masking description
Masking is not used because the study is an earlyphase cell-therapy trial focused on safety, dose finding, feasibility, pharmacodynamics, and preliminary efficacy.
Intervention model description
Multicenter, open-label, biomarker-informed study with Part A (standard 3+3 dose-escalation) followed by Part B (dose expansion at the RP2D). All treated participants receive the same investigational dual-target CAR-NK product after baseline assessment of GD2 and B7-H3 expression. Biomarker analyses are prespecified to explore which antigen profile appears most suitable for later-stage development.
Eligibility
Sex/Gender
ALL
Age
12 Months to 21 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of dose-limiting toxicities (DLTs) after first CARNK infusion, using protocol-defined DLT criteria. | 28 days | — |
| Incidence and severity of treatment-emergent adverse events | 12 months | Incidence and severity of treatment-emergent adverse events, including CRS and ICANS, graded using CTCAE v5.0 and ASTCT consensus criteria. |
Secondary
| Measure | Time frame |
|---|---|
| Objective response rate by revised International Neuroblastoma Response Criteria (rINRC). | 12 months |
| Duration of response among responders | 24 months |
| Progression-free survival | 12 months |
| Overall survival | 24 months |
Countries
China
Contacts
CONTACTSeni S Lu, Phd
Outcome results
None listed