Passive immunotherapy experience in patients with high-risk neuroblastoma

Introduction. Despite great achievements in treatment of neuroblastoma (NB) for the last decades, the outcome for high-risk patients remains adverse: 5-year overall survival does not exceed 30 %.

The purpose of the study. Demonstration of anti-GD2 monoclonal antibodies immunotherapy and assessment of its toxicity in patients treated at the N.N. Petrov National Medical Research Center of Oncology.

Material and methods. Anti-GD2 antibodies have been used as post consolidation in 8 high-risk NB patients aged from 1.8 to 10 years old since 2018 to present. After completion of induction chemotherapy according to NB-2004protocol, all patients underwent local tumor control with surgery and additional local radiotherapy in 3 cases. Four patients were received a single high-dose chemotherapy with autologous bone marrow transplant; one patient was received high-dose chemotherapy with haploidentical stem cell transplantation. Tree patients were received the tandem high-dose chemotherapy with autologous stem-cell transplantation. Two (25 %) patients had a primary resistant NB, and remission was achieved only after three lines of chemotherapy. One (12.5 %) child was diagnosed with a recurrence of NB of a solitary lesion in the right frontal lobe of the brain 8 months after the completion of the treatment according to the NB-2004protocol. Thus, 3 people from the study group received anti-GD2 antibodies after applying several lines of chemotherapy. All children at the start ofanti-GD2 antibody therapy were no progressive disease.

Results. A total of 21 courses of immunotherapy were conducted. No progressive disease was the main condition of anti-GD2 antibodies immunotherapy, such patients were excluded from the research. The antibodies were administered as a continuous infusion during 10 days (240 hours) in a daily dose of 10 mg/m2. When using the antibodies, the following adverse events were noted: hematotoxicity in 90.4 % cases, fever in 71.4 %, diarrhea in 23.8 %, capillary leak syndrome in 19 % patients, neuropathy and cytokine release syndrome were detected in 14.9 % cases, pain — in 9.5 % patients. All complications were tolerable and cured, dose reduction was not required. Now 7patients are in remission, in one patient after the first cycle of immunotherapy progressive disease was revealed.

Conclusions. The immunotherapy monoclonal anti-GD2 antibodies are well tolerable and safe procedure with adequate maintenance therapy. According to international experience the efficiency does not raise her doubts.

1. Esposito M.R., Aveic S., Seydel A., Tonini G.P. Neuroblastoma treatment in the post-genomic era. J Biomed Sci 2017;24:14. doi: 10.1186/s12929-017-0319-y.

2. McGinty L., Kolesar J. Dinutuximab for maintenance therapy in pediatric neuroblastoma. Am J Health Syst Pharm 2017;74(8):563-7. doi: 10.2146/ajhp160228.

3. Kushner B., Kramer K. Successful multifold dose escalation of anti-GD2 monoclonal antibody 3F8 in patients with neuroblastoma: a phase I study. J Clin Oncol 2011;29:1168-74. PMID: 21343563.

4. Wu Z.L., Schwartz E., Seeger R., Seeger R., Ladisch S. Expression of GD2 ganglioside by untreated primary human neuroblastomas. Cancer Res 1986;46:440-3. PMID: 3940209.

5. Kholodenko I.V., Doronin I.I., Kholodenko R.V. Clinical trials of antibodies to ganglioside GD2 for antitumor therapy: perspectives and limitations. Sovremennyye problemy dermatovenerologii, immunologii i vrachebnoy kosmetologii = Modern Problems of Dermatovenerology, Immunology and Medical Cosmetology 2010;6(1):79-83. (In Russ.).

6. Cheresh D.A., Pierschbacher M.D., Herzig M.A., Mujoo K. Disialogangliosides GD2 and GD3 are involved in the attachment of human melanoma and neuroblastoma cells to extracellular matrix proteins. J Cell Biol 1986;102:688-96. PMID: 3005335.

7. Barry W.E., Jackson J.R., Asuelime G.E., Wu H.W., Sun J., Wan Z., Malvar J., Sheard M.A., Wang L., Seeger R.C., Kim E.S. Activated Natural Killer Cells in Combination with Anti-GD2 Antibody Dinutuximab Improve Survival of Mice after Surgical Resection of Primary Neuroblastoma. Clin Cancer Res 2019;25(1):325-33. doi: 10.1158/1078-0432.CCR-18-1317.

8. Horta Z.P., Goldberg J.L., Sondel P.M. Anti-GD2 mAbs and next-generation mAb-based agents for cancer therapy Immunotherapy 2016;8(9):1097-117. doi: 10.2217/imt-2016-0021.

9. Simon Т., Hero В., Faldum А., Handgretinger R., Schrappe М., Klingebiel Т., Berthold F. Long term outcome of high-risk neuroblastoma patients after immunotherapy with antibody ch14.18 or oral metronomic chemotherapy. BMC Cancer 2011;11:21. doi: 10.1186/1471-2407-11-21.

10. Ladenstein R., Potschger U., Valteau-Couanet D., Luksch R., Castel V., Yaniv I., Laureys G., Brock P, Michon J.M., Owens C., Trahair T., Chan G.C.F., Ruud E., Schroeder H., Popovic M.B., Schreier G., Loibner H., Ambros P., Holmes K., Castellani R.M., Gaze M.N., Garaventa A., Pearson A., Lode H.N. Interleukin 2 with anti-GD2 antibody ch14.18/CHO (dinutuximab beta) in patients with high-risk neuroblastoma (HR-NBL1/SIOPEN): a multicentre, randomised, phase 3 trial. Lancet Oncol 2018;19(12):1617-29. doi.org/10.1016/S1470-2045(18)30578-3.

11. Keyel M.E., Reynolds C.P. Spotlight on dinutuximab in the treatment of high-risk neuroblastoma: development and place in therapy. Biologics 2019;13:1-12. doi: 10.2147/BTT.S114530.

12. Peinemann F., van Dalen E.C., Enk H., Tytgat G. A. Anti-GD2 antibody-containing immunotherapy post-consolidation therapy for people with high-risk neuroblastoma treated with autologous haematopoietic stem cell transplantation. Cochrane Database Syst Rev 2019;24(4):124-42. doi: 10.1002/14651858.CD012442.

13. Navid F., Sondel P.M., Barfield R., Shulkin B.L., Kaufman R.A., Allay J.A., Gan J., Hutson P., Seo S., Kim K.M., Goldberg J., Hank J.A., Billups C.A., Wu J., Furman W.L., McGregor L., Otto M., Gillies S.D., Handgretinger R., Santana V.M. Phase I trial of a novel anti-GD2 monoclonal antibody, hu14.18K322A, designed to decrease toxicity in children with refractory or recurrent neuroblastoma. J Clin Oncol 2014;32(14):1445-52. doi: 10.1200/JCO.2013.50.4423.

14. Smith V., Foster J. High-risk neuroblastoma treatment review. Children (Basel) 2018;5(9). pii: E114. doi: 10.3390/children5090114.

15. Khizhnikov A.V., Kazantsev A.P. Treatment of high-risk neuroblastoma. Onkopediatriya = Oncopediatrics 2017;4(2):131-40. (In Russ.).

16. Ploessl C., Pan A., Maples K.T., Lowe D.K. Dinutuximab: An Anti-GD2 Monoclonal Antibody for High-Risk Neuroblastoma. Ann Pharmacother 2016;50(5):416-22. doi: 10.1177/1060028016632013.