A Pilot Trial of Humanized Anti-GD2 Monoclonal Antibody (hu14.18K322A) with Chemotherapy and Natural Killer Cells in Children with Recurrent/Refractory Neuroblastoma

Clin Cancer Res. 2017 Nov 1;23(21):6441-6449. doi: 10.1158/1078-0432.CCR-17-0379. Epub 2017 Sep 22.

Abstract

Purpose: Anti-GD2 mAbs, 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 (40 mg/m2/dose, days 2-5), GM-CSF, and IL2 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 IL2 receptor alpha (sIL2Rα) levels, and human antihuman 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 complete responses, 1 very good partial response, 3 partial responses) and five had stable disease. The median time to progression was 274 days (range, 239-568 days); 10 of 13 patients (77%) survived 1 year. Hu14.18K322A pharmacokinetics was not affected by chemotherapy or HAHA. All patients had increased sIL2Rα 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. Clin Cancer Res; 23(21); 6441-9. ©2017 AACR.

Publication types

  • Clinical Trial, Phase I

MeSH terms

  • Adolescent
  • Antibodies, Monoclonal, Humanized / administration & dosage*
  • Antibodies, Monoclonal, Humanized / adverse effects
  • Antibodies, Monoclonal, Humanized / pharmacokinetics
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Camptothecin / administration & dosage
  • Camptothecin / analogs & derivatives
  • Carboplatin / administration & dosage
  • Cell- and Tissue-Based Therapy*
  • Child
  • Child, Preschool
  • Combined Modality Therapy
  • Cyclophosphamide / administration & dosage
  • Dacarbazine / administration & dosage
  • Dacarbazine / analogs & derivatives
  • Disease-Free Survival
  • Drug-Related Side Effects and Adverse Reactions / blood
  • Drug-Related Side Effects and Adverse Reactions / classification
  • Drug-Related Side Effects and Adverse Reactions / pathology
  • Etoposide / administration & dosage
  • Female
  • Gangliosides / antagonists & inhibitors*
  • Gangliosides / immunology
  • Humans
  • Ifosfamide / administration & dosage
  • Infant
  • Interleukin-2 / blood
  • Interleukin-2 Receptor alpha Subunit / blood
  • Irinotecan
  • Killer Cells, Natural / immunology
  • Male
  • Neoplasm Recurrence, Local / blood
  • Neoplasm Recurrence, Local / drug therapy*
  • Neoplasm Recurrence, Local / pathology
  • Neuroblastoma / blood
  • Neuroblastoma / drug therapy*
  • Neuroblastoma / pathology
  • Temozolomide
  • Topotecan / administration & dosage
  • Treatment Outcome

Substances

  • Antibodies, Monoclonal, Humanized
  • Gangliosides
  • IL2 protein, human
  • IL2RA protein, human
  • Interleukin-2
  • Interleukin-2 Receptor alpha Subunit
  • sialogangliosides
  • Etoposide
  • Irinotecan
  • Dacarbazine
  • Topotecan
  • Cyclophosphamide
  • Carboplatin
  • Ifosfamide
  • Camptothecin
  • Temozolomide