Purpose: Preclinical studies demonstrate that anti-GD2 antibodies, acting via antibody-dependent cell-mediated cytotoxicity (ADCC), enhance the effects of chemotherapy. We conducted a safety trial of a fixed dose of hu14.18K322A and 3 different chemotherapy combinations with parental NK cells to enhance ADCC.
Methods: Children with recurrent/refractory neuroblastoma received up to six courses of hu14.18K322A (40mg/m2/dose, days 2-5) with GMCSF and low-dose IL-2 in combination with chemotherapy: cyclophosphamide/topotecan (courses 1,2), irinotecan/temozolomide (courses 3,4) and ifosfamide/carboplatin/etoposide (courses 5,6). Parental NK cells were administered with courses 2, 4 and 6. Serial serum hu14.18K322A pharmacokinetic studies and soluble IL-2 receptor (sIL2R) levels were obtained during each course.
Results: Thirteen heavily pretreated patients (5 males; median age 5.4 yrs; range 1.9-1 - 3.5yrs), including 9 with prior anti-GD2 treatment, 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 and myelodysplastic syndrome). Common toxicities included grade 3/4 myelosupression (13/13 patients) and grade 1/2 pain (13/13 patients). Eleven patients received 29 NK cell infusions. The median number of NK cells infused per dose was 15.5x106/kg (range, 4.7x106/kg - 59.5x106/kg). All patients had an increase in sIL2R levels, indicative of immune activation. The overall response rate was 61.5%: 4 complete responses, 1 very good partial response, 3 partial responses and 5 with stable disease. The median time to progression was 256 days (range 33 - 553days); one-year overall survival was 75.5% (95% C.I., 50.9 - 100%). Median hu14.18K322A α (initial phase) half-life was ~27hours.
Conclusions: Administration of chemotherapy with Hu14.18K322A and parental NK cells is safe, feasible and resulted in clinically meaningful responses in patients with refractory/recurrent neuroblastoma. Further studies are warranted of this approach in newly diagnosed patients.