Παρασκευή 22 Σεπτεμβρίου 2017

A pilot trial of humanized anti-GD2 monoclonal antibody (hu14.18K322A) with chemotherapy and natural killer cells in children with recurrent/refractory neuroblastoma

Purpose: Anti-GD2 monoclonal antibodies (mAb), acting via antibody-dependent cell-mediated cytotoxicity, may enhance the effects of chemotherapy. This pilot trial investigated a fixed dose of a unique anti-GD2 mAb, hu14.18K322A, combined with chemotherapy, cytokines and haploidentical natural killer (NK) cells. Experimental Design: Children with recurrent/refractory neuroblastoma received up to six courses of hu14.18K322A (40mg/m2/dose, days 2-5), GMCSF and IL-2 with chemotherapy: cyclophosphamide/topotecan (courses 1,2), irinotecan/temozolomide (courses 3,4) and ifosfamide/carboplatin/etoposide (courses 5,6). Parentally-derived NK cells were administered with courses 2, 4 and 6. Serum for pharmacokinetic studies of hu14.18K322A, soluble IL-2 receptor alpha (sIL-2Ra) levels and human anti-human antibodies (HAHA) were obtained. Results: Thirteen heavily pretreated patients (9 with prior anti-GD2 therapy) completed 65 courses. One patient developed an unacceptable toxicity (grade 4 thrombocytopenia >35 days). Four patients discontinued treatment for adverse events (hu14.18K322A allergic reaction, viral infection, surgical death, second malignancy). Common toxicities included grade 3/4 myelosuppression (13/13 patients) and grade 1/2 pain (13/13 patients). Eleven patients received 29 NK cell infusions. The response rate was 61.5% (4 CR, 1 VGPR, 3 PR) and 5 had stable disease. The median time to progression was 274 days (range, 239-568 days); 10 of 13 patients (77%) survived one year. Hu14.18K322A pharmacokinetics were not affected by chemotherapy or HAHA. All patients had increased sIL-2Ra levels, indicating immune activation. Conclusions: Chemotherapy plus hu14.18K322A, cytokines and NK cells is feasible and resulted in clinically meaningful responses in patients with refractory/recurrent neuroblastoma. Further studies of this approach are warranted in patients with relapsed and newly-diagnosed neuroblastoma.



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