Tolerability, response and outcome of high-risk neuroblastoma patients treated with long-term infusion of anti-GD2 antibody ch14.18/CHO.

Abstract

Immunotherapy with short term infusion (STI) of monoclonal anti-GD2 antibody (mAb) ch14.18 (4 × 25 mg/m2/d; 8-20 h) in combination with cytokines and 13-cis retinoic acid (RA) prolonged survival in high-risk neuroblastoma (NB) patients. Here, we investigated long-term infusion (LTI) of ch14.18 produced in Chinese hamster ovary cells (ch14.18/CHO; 10 × 10 mg/m2; 24 h) in combination with subcutaneous (s.c.) interleukin-2 (IL-2) in a single center program and report clinical response, toxicity and survival. Fifty-three high-risk NB patients received up to 6 cycles of 100 mg/m2 ch14.18/CHO (d8-17) as LTI combined with 6 × 106 IU/m2 s.c. IL-2 (d1-5; 8-12) and 160 mg/m2 oral RA (d19-32). Pain toxicity was documented with validated pain scores and intravenous (i.v.) morphine usage. Response was assessed in 37/53 evaluable patients following International Neuroblastoma Risk Group criteria. Progression-free (PFS) and overall survival (OS) was analyzed by the Kaplan-Meier method and compared to a matched historical control group from the database of AIEOP, the "Italian Pediatric Ematology and Oncology Association". LTI of ch14.18/CHO showed acceptable toxicity profile indicated by low pain scores, reduced i.v. morphine usage and low frequency of Grade ≥3 adverse events that allowed outpatient treatment. We observed a best response rate of 40.5% (15/37; 5 CR, 10 PR), 4-year (4 y) PFS of 33.1% (observation 0.1- 4.9 y, mean: 2.2 y) and a 4 y OS of 47.7% (observation 0.27 - 5.20 y, mean: 3.6 y). Survival of the entire cohort (53/53) and the relapsed patients (29/53) was significantly improved compared to historical controls. LTI of ch14.18/CHO thus shows an acceptable toxicity profile, objective clinical responses and a strong signal of clinical efficacy in NB patients.

• Authors: Ina Mueller, Karoline Ehlert, Stefanie Endres, Lena Pill, Nikolai Siebert, Silke Kietz, Penelope Brock, Alberto Garaventa, Dominique Valteau-Couanet, Evelyne Janzek, Norbert Hosten, Andreas Zinke, Winfried Barthlen, Emine Varol, Hans Loibner, Ruth Ladenstein, Holger N Lode
• Journal: mAbs (MAbs) Vol. 10 Issue 1 Pg. 55-61 (01 2018) ISSN: 1942-0870 [Electronic] United States
• PMID: 29120699 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antineoplastic Agents, Immunological
• Gangliosides
• Interleukin-2
• ganglioside, GD2
• dinutuximab
• Isotretinoin

Topics

• Adolescent
• Adult
• Antibodies, Monoclonal (administration & dosage, adverse effects)
• Antineoplastic Agents, Immunological (administration & dosage, adverse effects)
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• Child
• Child, Preschool
• Drug Administration Schedule
• Female
• Gangliosides (immunology)
• Humans
• Immunotherapy (adverse effects, methods)
• Infant
• Infusions, Intravenous
• Interleukin-2 (administration & dosage)
• Isotretinoin (administration & dosage)
• Male
• Neuroblastoma (immunology, mortality, pathology, therapy)
• Progression-Free Survival
• Time Factors
• Treatment Outcome
• Young Adult