GD2-направленная иммунотерапия нейробластомы группы высокого риска с использованием химерных антител ch14.18

Нейробластома является наиболее частой экстракраниальной солидной опухолью у детей от 0 до 14 лет. Современные риск-адаптированные программы лечения основаны на выделении 3 групп риска. В группу высокого риска стратифицируются 40–50% пациентов. Прогноз у пациентов группы высокого риска остается неблагоприятным (вероятность долгосрочной выживаемости менее 50%), несмотря на применение агрессивной мультимодальной терапии, включающей высокодозную химиотерапию и аутологичную трансплантацию гемопоэтических стволовых клеток. В большинстве случаев опухолевые клетки при нейробластоме экспрессируют дисиалоганглиозид GD2, рассматривающийся как возможная мишень для проведения иммунотерапии. На протяжении последних 30 лет были разработаны и внедрены в клиническую практику GD2-направленные химерные моноклональные антитела ch14.18. Целым рядом клинических исследований было показано улучшение прогноза у пациентов с нейробластомой группы высокого риска при использовании моноклональных антител ch14.18, в первую очередь за счет эрадикации минимальной остаточной популяции опухолевых клеток, резистентных к стандартной химиотерапии. Настоящий обзор литературы обобщает международный опыт применения моноклональных антител ch14.18 от ранних фаз клинических исследований до крупных рандомизированных исследований, позволивших рассматривать иммунотерапию как важный компонент мультимодальной терапии нейробластомы группы высокого риска. Рассмотрены перспективы применения и место иммунотерапии в первой линии терапии у пациентов с нейробластомой группы высокого риска и у больных с рецидивами заболевания.

дети, нейробластома, GD2, иммунотерапия, моноклональные антитела

1. Spix C., Pastore G., Sankila R., Stiller C.A., Steliarova-Foucher E. Neuroblastoma incidence and survival in European children (1978–1997): report from the Automated Childhood Cancer Information System project. Eur J Cancer 2006; 42 (13): 2081–91. DOI: 10.1016/j.ejca.2006.05.008

2. Kaatsch P., Spix C. German Childhood Cancer Registry – Annual Report 2015 (1980– 2014). Mainz: Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI) at the University Medical Center of the Johannes Gutenberg University Mainz; 2015.

3. Pinto N.R., Applebaum M.A., Volchenboum S.L., Matthay K.K., London W.B., Ambros P.F., et al. Advances in Risk Classification and Treatment Strategies for Neuroblastoma. J Clin Oncol 2015; 33 (27): 3008–17. DOI: 10.1200/JCO.2014.59.4648

4. Matthay K.K., Maris J.M., Schleiermacher G., Nakagawara A., Mackall C.L., Diller L., et al. Neuroblastoma. Nat Rev Dis Primers 2016; 2: 16078. DOI: 10.1038/nrdp.2016.78

5. Matthay K.K., Reynolds C.P., Seeger R.C., Shimada H., Adkins E.S., Haas-Kogan D., et al. Long-term results for children with high-risk neuroblastoma treated on a randomized trial of myeloablative therapy followed by 13-cis-retinoic acid: a children's oncology group study. J Clin Oncol 2009; 27 (7): 1007–13. DOI: 10.1200/JCO.2007.13.8925

6. Valteau-Couanet D., Le Deley M.C., Bergeron C., Ducassou S., Michon J., Rubie H., et al. Long-term results of the combination of the N7 induction chemotherapy and the busulfan-melphalan high dose chemotherapy. Pediatr Blood Cancer 2014; 61 (6): 977–81. DOI: 10.1002/pbc.24713

7. Berthold F., Faldum A., Ernst A., Boos J., Dilloo D., Eggert A., et al. Extended induction chemotherapy does not improve the outcome for high-risk neuroblastoma patients: results of the randomized open-label GPOH trial NB2004-HR. Ann Oncol 2020; 31 (3): 422–9. DOI: 10.1016/j.annonc.2019.11.011

8. Matthay K.K., Atkinson J.B., Stram D.O., Selch M., Reynolds C.P., Seeger R.C. Patterns of relapse after autologous purged bone marrow transplantation for neuroblastoma: a Childrens Cancer Group pilot study. J Clin Oncol 1993; 11 (11): 2226–33. DOI: 10.1200/JCO.1993.11.11.2226

9. Качанов Д.Ю. Результаты рискадаптированной терапии нейробластомы у детей. Автореф. дис. … д-ра мед. наук. М.; 2018.

10. Park J.A., Cheung N.V. Targets and Antibody Formats for Immunotherapy of Neuroblastoma. J Clin Oncol 2020; 38 (16): 1836–48. DOI: 10.1200/JCO.19.01410

11. Modak S., Cheung N.K. Disialoganglioside directed immunotherapy of neuroblastoma. Cancer Invest 2007; 25 (1): 67–77. DOI: 10.1080/07357900601130763

12. Sait S., Modak S. Anti-GD2 immunotherapy for neuroblastoma. Expert Rev Anticancer Ther 2017; 17 (10): 889–904. DOI: 10.1080/14737140.2017.1364995

13. Kholodenko I.V., Kalinovsky D.V., Doronin I.I., Deyev S.M., Kholodenko R.V. Neuroblastoma Origin and Therapeutic Targets for Immunotherapy. J Immunol Res 2018; 2018: 7394268. DOI: 10.1155/2018/7394268

14. Yanagisawa M., Yoshimura S., Yu R.K. Expression of GD2 and GD3 gangliosides in human embryonic neural stem cells. ASN Neuro 2011; 3 (2): e00054. DOI: 10.1042/AN20110006

15. Lammie G.A., Cheung N.K.V., Gerald W., Rosenblum M., Cordon-Cardo C. Ganglioside GD2 expression in the human nervous system and in neuroblastomas - an immunohistochemical study. Int J Oncol 1993; 3 (5): 909–15. DOI: 10.3892/ijo.3.5.909

16. Wondimu A., Liu Y., Su Y., Bobb D., Ma J.S., Chakrabarti L., Radoja S., et al. Gangliosides drive the tumor infiltration and function of myeloid-derived suppressor cells. Cancer Res 2014; 74 (19): 5449–57.

17. Dobrenkov K., Ostrovnaya I., Gu J., Cheung I.Y., Cheung N.K. Oncotargets GD2 and GD3 are highly expressed in sarcomas of children, adolescents, and young adults. Pediatr Blood Cancer 2016; 63 (10): 1780–5.

18. Wu Z., Schwartz E., Seeger R.C., Ladisch S. Expression of GD2 ganglioside by untreated primary human neuroblastomas. Cancer Res 1986; 46 (1): 440–3.

19. Balis F.M., Busch C.M., Desai A.V., Hibbitts E., Naranjo A., Bagatell R., et al. The ganglioside G(D2) as a circulating tumor biomarker for neuroblastoma. Pediatr Blood Cancer 2020; 67 (1): e28031. DOI: 10.1002/pbc.28031

20. Kramer K., Gerald W.L., Kushner B.H., Larson S.M., Hameed M., Cheung N.K. Disaloganglioside GD2 loss following monoclonal antibody therapy is rare in neuroblastoma. Med Pediatr Oncol 2001; 36 (1): 194–6. DOI: 10.1002/1096-911X(20010101)36:13.0.CO;2-B

21. Cheever M.A., Allison J.P., Ferris A.S., Finn O.J., Hastings B.M., Hecht T.T., et al. The prioritization of cancer antigens: a national cancer institute pilot project for the acceleration of translational research. Clin Cancer Res 2009; 15 (17): 5323–37. DOI: 10.1158/1078-0432.CCR-09-0737

22. Cheung N.K., Lazarus H., Miraldi F.D., Abramowsky C.R., Kallick S., Saarinen U.M., et al. Ganglioside GD2 specific monoclonal antibody 3F8: a phase I study in patients with neuroblastoma and malignant melanoma. J Clin Oncol. 1987; 5 (9): 1430–40. DOI: 10.1200/JCO.1987.5.9.1430

23. Cheung N.K., Cheung I.Y., Kushner B.H., Ostrovnaya I., Chamberlain E., Kramer K., et al. Murine anti-GD2 monoclonal antibody 3F8 combined with granulocyte-macrophage colony-stimulating factor and 13-cis-retinoic acid in high-risk patients with stage 4 neuroblastoma in first remission. J Clin Oncol 2012; 30 (26): 3264–70. DOI: 10.1200/JCO.2011.41.3807

24. Kushner B.H., Ostrovnaya I., Cheung I.Y., Kuk D., Modak S., Kramer K., et al. Lack of survival advantage with autologous stemcell transplantation in high-risk neuroblastoma consolidated by anti-GD2 immunotherapy and isotretinoin. Oncotarget 2016; 7 (4): 4155–66. DOI: 10.18632/oncotarget.6393

25. Yu A.L., Gilman A.L., Ozkaynak M.F., London W.B., Kreissman S.G, Chen H.X., et al. Children's Oncology Group. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med 2010; 363 (14): 1324–34. DOI: 10.1056/NEJMoa0911123

26. Ladenstein R., Pötschger U., Valteau-Couanet D., Luksch R., Castel V., Yaniv I., et al. 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: 10.1016/S1470-2045(18)30578-3

27. Ladenstein R., Pötschger U., ValteauCouanet D., Luksch R., Castel V., Ash S., et al. Investigation of the Role of Dinutuximab Beta-Based Immunotherapy in the SIOPEN High-Risk Neuroblastoma 1 Trial (HR-NBL1). Cancers (Basel) 2020; 12 (2): 309. DOI: 10.3390/cancers12020309

28. Gillies S.D., Lo K.M., Wesolowski J. Highlevel expression of chimeric antibodies using adapted cDNA variable region cassettes. J Immunol Methods 1989; 125 (1–2): 191–202. DOI: 10.1016/0022-1759(89)90093-8

29. Barker E., Mueller B.M., Handgretinger R., Herter M., Yu A.L., Reisfeld R.A. Effect of a chimeric anti-ganglioside GD2 antibody on cell-mediated lysis of human neuroblastoma cells. Cancer Res 1991; 51 (1): 144– 9.

30. Matthay K.K., George R.E., Yu A.L. Promising therapeutic targets in neuroblastoma. Clin Cancer Res 2012; 18 (10): 2740–53. DOI: 10.1158/1078-0432.CCR-11-1939

31. Doronin I.I., Vishnyakova P.A., Kholodenko I.V., Ponomarev E.D., Ryazantsev D.Y., Molotkovskaya I.M., et al. Ganglioside GD2 in reception and transduction of cell death signal in tumor cells. BMC Cancer 2014; 14: 295. DOI: 10.1186/1471-2407-14-295

32. Zeng Y., Fest S., Kunert R., Katinger H., Pistoia V., Michon J., et al. Anti-neuroblastoma effect of ch14.18 antibody produced in CHO cells is mediated by NK-cells in mice. Mol Immunol 2005; 42 (11): 1311–9. DOI: 10.1016/j.molimm.2004.12.018

33. Lode H.N., Xiang R., Dreier T., Varki N.M., Gillies S.D., Reisfeld R.A. Natural killer cell-mediated eradication of neuroblastoma metastases to bone marrow by targeted interleukin-2 therapy. Blood 1998; 91 (5): 1706–15.

34. Kushner B.H., Cheung N.K. GM-CSF enhances 3F8 monoclonal antibody-dependent cellular cytotoxicity against human melanoma and neuroblastoma. Blood 1989; 73 (7): 1936–41.

35. Handgretinger R., Anderson K., Lang P., Dopfer R., Klingebiel T., Schrappe M., et al. A phase I study of human/mouse chimeric antiganglioside GD2 antibody ch14.18 in patients with neuroblastoma. Eur J Cancer 1995; 31A (2): 261–7. DOI: 10.1016/0959-8049(94)00413-y

36. Yu A.L., Uttenreuther-Fischer M.M., Huang C.S., Tsui C.C., Gillies S.D., Reisfeld R.A., et al. Phase I trial of a humanmouse chimeric anti-disialoganglioside monoclonal antibody ch14.18 in patients with refractory neuroblastoma and osteosarcoma. J Clin Oncol 1998; 16(6): 2169- 80. DOI: 10.1200/JCO.1998.16.6.2169

37. Simon T., Hero B., Faldum A., Handgretinger R., Schrappe M., Niethammer D., et al. Consolidation treatment with chimeric anti-GD2-antibody ch14.18 in children older than 1 year with metastatic neuroblastoma. J Clin Oncol 2004; 22 (17): 3549–57. DOI: 10.1200/JCO.2004.08.143

38. Simon T., Hero B., Faldum A., Handgretinger R., Schrappe M., Klingebiel T., et al. 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

39. Simon T., Hero B., Faldum A., Handgretinger R., Schrappe M., Niethammer D., et al. Infants with stage 4 neuroblastoma: the impact of the chimeric anti-GD2-antibody ch14.18 consolidation therapy. Klin Padiatr 2005; 217 (3): 147–52. DOI: 10.1055/s-2005-836518

40. Ozkaynak M.F., Sondel P.M., Krailo M.D., Gan J., Javorsky B., Reisfeld R.A., et al. Phase I study of chimeric human/murine anti-ganglioside G(D2) monoclonal antibody (ch14.18) with granulocyte-macrophage colony-stimulating factor in children with neuroblastoma immediately after hematopoietic stem-cell transplantation: A Children's Cancer Group Study. J Clin Oncol 2000; 18 (24): 4077–85. DOI: 10.1200/JCO.2000.18.24.4077

41. Gilman A.L., Ozkaynak M.F., Matthay K.K., Krailo M., Yu A.L., Gan J., et al. Phase I study of ch14.18 with granulocyte-macrophage colony-stimulating factor and interleukin-2 in children with neuroblastoma after autologous bone marrow transplantation or stem-cell rescue: a report from the Children's Oncology Group. J Clin Oncol 2009; 27 (1): 85–91. DOI: 10.1200/JCO.2006.10.3564

42. Ozkaynak M.F., Gilman A.L., London W.B., Naranjo A., Diccianni M.B., Tenney S.C., et al. A Comprehensive Safety Trial of Chimeric Antibody 14.18 With GM-CSF, IL-2, and Isotretinoin in High-Risk Neuroblastoma Patients Following Myeloablative Therapy: Children's Oncology Group Study ANBL0931. Front Immunol 2018; 9: 1355. DOI: 10.3389/fimmu.2018.01355

43. Park J.R., Bagatell R., London W.B., Maris J.M., Cohn S.L., Mattay K.K., et al. COG Neuroblastoma Committee. Children's Oncology Group's 2013 blueprint for research: neuroblastoma. Pediatr Blood Cancer 2013; 60 (6): 985–93. DOI: 10.1002/pbc.24433

44. Dhillon S. Dinutuximab: first global approval. Drugs 2015; 75 (8): 923–7. DOI: 10.1007/s40265-015-0399-5

45. Yu A.L., Gilman A.L., Ozkaynak M.F., Sondel P.M., London W.B., Cretella S., et al. Update of Outcome for High-Risk Neuroblastoma Treated on a Randomized Trial of chimeric Anti-GD2 Antibody (ch14.18) + GM-CSF / IL2 Immunotherapy in 1st Response: A Children's Oncology Group Study. Proceedings of the Advances in Neuroblastoma Research Congress 2014. Cologne, Germany. P. 108. Web access. https://www.anrmeeting.org/dl/ANR20 14/ANR_20 14_Information_Book_2014- 05-08.pdf

46. Ladenstein R., Weixler S., Baykan B., Bleeke M., Kunert R., Katinger D., et al. Ch14.18 antibody produced in CHO cells in relapsed or refractory Stage 4 neuroblastoma patients: a SIOPEN Phase 1 study. MAbs 2013; 5 (5): 801–9. DOI: 10.4161/mabs.25215

47. Ladenstein R., Valteau-Couanet D., Brock P., Yaniv I., Castel V., Laureys G., et al. Randomized Trial of prophylactic granulocyte colony-stimulating factor during rapid COJEC induction in pediatric patients with high-risk neuroblastoma: The European HR-NBL1/SIOPEN study. J Clin Oncol 2010; 28 (21): 3516–24. DOI: 10.1200/JCO.2009.27.3524

48. Ladenstein R., Pötschger U., Siabalis D., Garaventa A., Bergeron C., Lewis I.J., et al. Dose finding study for the use of subcutaneous recombinant interleukin-2 to augment natural killer cell numbers in an outpatient setting for stage 4 neuroblastoma after megatherapy and autologous stemcell reinfusion. J Clin Oncol 2011; 29 (4): 441–8. DOI: 10.1200/JCO.2009.23.5465

49. Siebert N., Eger C., Seidel D., Jüttner M., Zumpe M., Wegner D., et al. Pharmacokinetics and pharmacodynamics of ch14.18/CHO in relapsed/refractory highrisk neuroblastoma patients treated by long-term infusion in combination with IL-2. MAbs 2016; 8 (3): 604–16. DOI: 10.1080/19420862.2015

50. Mueller I., Ehlert K., Endres S., Pill L., Siebert N., Kietz S., et al. Tolerability, response and outcome of high-risk neuroblastoma patients treated with long-term infusion of anti-GD(2) antibody ch14.18/ CHO. MAbs 2018; 10 (1): 55–61. DOI: 10.1080/19420862.2017.1402997

51. Ladenstein R., Poetschger U., Valteau-Couanet D., Gray J., Luksch R., Balwierz W., et al. Randomization of dose-reduced subcutaneous interleukin-2 (scIL2) in maintenance immunotherapy (IT) with anti-GD2 antibody dinutuximab beta (DB) long-term infusion (LTI) in front–line highrisk neuroblastoma patients: Early results from the HR-NBL1/SIOPEN trial. J Clin Oncol 2019; 37 (15): 10013.

52. Siebert N., Jensen C., Troschke-Meurer S., Zumpe M., Jüttner M., Ehlert K., et al. Neuroblastoma patients with high-affinity FCGR2A, -3A and stimulatory KIR 2DS2 treated by long-term infusion of anti-GD2 antibody ch14.18/CHO show higher ADCC levels and improved event-free survival. Oncoimmunology 2016; 5 (11): e1235108. DOI: 10.1080/2162402X.2016.1235108

53. Terzic T., Cordeau M., Herblot S., Teira P., Cournoyer S., Beaunoyer M., et al. Expression of Disialoganglioside (GD2) in Neuroblastic Tumors: A Prognostic Value for Patients Treated with Anti-GD2 Immunotherapy. Pediatr Dev Pathol 2018; 21 (4): 355–62. DOI: 10.1177/1093526617723972

54. Osenga K.L., Hank J.A., Albertini M.R., Gan J., Sternberg A.G., Eickhoff J., et al. Children's Oncology GroupA phase I clinical trial of the hu14.18-IL2 (EMD 273063) as a treatment for children with refractory or recurrent neuroblastoma and melanoma: a study of the Children's Oncology Group. Clin Cancer Res 2006; 12 (6): 1750–9. DOI: 10.1158/1078-0432.CCR-05-2000

55. Shusterman S., London W., Gillies S., Hank J., Voss S., Seeger R., et al. Antitumor activity of hu14.18-IL2 in patients with relapsed/refractory neuroblastoma: a Children's Oncology Group (COG) phase II study. J Clin Oncol 2010; 28 (33): 4969–75. DOI: 10.1200/JCO.2009.27.8861

56. Bagatell R., London W.B., Wagner L.M., Voss S.D., Stewart C.F., Maris J.M., et al. Phase II study of irinotecan and temozolomide in children with relapsed or refractory neuroblastoma: a Children's Oncology Group study. J Clin Oncol 2011; 29 (2): 208– 13. DOI: 10.1200/JCO.2010.31.7107

57. Mody R., Naranjo A., Ryn C., Yu A., London W., Shulkin B., et al. Irinotecan-temozolomide with temsirolimus or dinutuximab in children with refractory or relapsed neuroblastoma (COG ANBL1221): an open-label, randomised, phase 2 trial. Lancet Oncol 2017; 18 (7): 946–57. DOI: 10.1016/S1470-2045(17)30355-8

58. Mody R., Yu A., Naranjo A., Zhang F.F., London W.B., Shulkin B.L., et al. Irinotecan, Temozolomide, and Dinutuximab With GM-CSF in Children With Refractory or Relapsed Neuroblastoma: A Report From the Children’s Oncology Group. J Clin Oncol 2020; 38 (19): 2160–9. DOI: 10.1200/JCO.20.00203

59. Iwai T., Sugimoto M., Wakita D., Yorozu K., Kurasawa M., Yamamoto K. Topoisomerase I inhibitor, irinotecan, depletes regulatory T cells and up-regulates MHC class I and PD-L1 expression, resulting in a supra-additive antitumor effect when combined with anti-PD-L1 antibodies Oncotarget 2018; 9 (59): 31411–21. DOI: 10.18632/oncotarget.25830

60. Heynckes S., Daka K., Franco P., Gaebelein A., Frenking H.J., Doria-Medina R., et al. Crosslink between temozolomide and PD-L1 immune-checkpoint inhibition in glioblastoma multiforme. BMC Cancer 2019; 19 (1): 117. DOI: 10.1186/s12885-019-5308-y

61. Federico S.M., McCarville M.B., Shulkin B., Sondel P., Hank J.A., Hutson P., et al. 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; 23 (21): 6441–9. DOI: 10.1158/1078-0432.CCR-17-0379

62. Kanold J., Paillard C., Tchirkov A., Merlin E., Marabelle A., Lutz P., et al. Allogeneic or haploidentical HSCT for refractory or relapsed solid tumors in children: toward a neuroblastoma model. Bone Marrow Transplant 2008; 42 Suppl 2: S25–30. DOI: 10.1038/bmt.2008.279

63. Lang P., Pfeiffer M., Müller I., Schumm M., Ebinger M., Koscielniak E., et al. Haploidentical stem cell transplantation in patients with pediatric solid tumors: preliminary results of a pilot study and analysis of graft versus tumor effects. Klin Padiatr 2006; 218 (6): 321–6. DOI: 10.1055/s-2006-942256

64. Illhardt T., Toporski J., Feuchtinger T., Turkiewicz D., Teltschik H., Ebinger M., et al. Haploidentical Stem Cell Transplantation for Refractory/Relapsed Neuroblastoma. Biol Blood Marrow Transplant 2018; 24 (5): 1005–12. DOI: 10.1016/j.bbmt.2017.12.805

65. Lang P., Illhardt T., Ebinger M., Schlegel P., Teltschik H.M., Feuchtinger T., et al. Haploidentical stem cell transplantation and subsequent immunotherapy with antiGD2 antibody for patients with relapsed metastatic neuroblastoma. J Clin Oncol 2015; 33 (15 Suppl): 10056. DOI: 10.1200/jco.2015.33.15_suppl.10056

66. European Medicines Agency. European public assessment report (EPAR), Committee for Medicinal Products for Human Use (CHMP) assessment report: Dinutuximab beta Apeiron (Qarziba®), EMA/263814/2017, 23 March 2017.

67. Barcikowski J., Fitzgerald M.P., Jaffe A.M., Mowery D. Poster 463 Unexpected Transverse Myelitis after Dinutuximab Therapy for Relapsed Neuroblastoma: A Case Report. PM R 2016; 8 (9S): S311. DOI: 10.1016/j.pmrj.2016.07.384

68. Ding Y.Y., Panzer J., Maris J.M., Castañeda A., Gomez-Chiari M., Mora J. Transverse myelitis as an unexpected complication following treatment with dinutuximab in pediatric patients with high-risk neuroblastoma: A case series. Pediatr Blood Cancer 2018; 65 (1). DOI: 10.1002/pbc.26732

69. Siebert N., Troschke-Meurer S., Marx M., Zumpe M., Ehlert K., Gray J., et al. Impact of HACA on Immunomodulation and Treatment Toxicity Following ch14.18/CHO Long-Term Infusion with Interleukin-2: Results from a SIOPEN Phase 2 Trial. Cancers (Basel) 2018; 10 (10): 387. DOI: 10.3390/cancers10100387

70. Kramer K., Kushner B.H., Modak S., Pandit-Taskar N., Tomlinson U., Wolden S.L., et al. A curative approach to central nervous system metastases of neuroblastoma. J Clin Oncol 2017; 35 (15): 10545. DOI: 10.1200/JCO.2017.35.15_suppl.10545

71. Lode H., Eggert A., Ladenstein R., Riesebeck S., Siebert N., Dworzak M., et al. Combination of Ch14.18/CHO and GPOH Induction Chemotherapy Cycles in Refractory Relapsed or Progressing High Risk Neuroblastoma Patients. Proceedings of the Advances in Neuroblastoma Research Congress 2018. San Francisco, USA; 2014. P. 61.

72. Furman W.L., Federico S.M., McCarville M.B., Shulkin B.L., Davidoff A.M., Krasin M.J., et al. A Phase II Trial of Hu14.18K322A in Combination with Induction Chemotherapy in Children with Newly Diagnosed High-Risk Neuroblastoma. Clin Cancer Res 2019; 25 (21): 6320–8. DOI: 10.1158/1078-0432.CCR-19-1452

73. ClinicalTrials.gov Identifier: NCT04385277. Treatment With Dinutuximab in Combination With Irinotecan and Temozolomide After Intensive Therapy for People With High-Risk Neuroblastoma. Assessed 15.07.2020.

74. Siebert N., Zumpe M., Jüttner M., Troschke-Meurer S., Lode H.N.. PD-1 blockade augments anti-neuroblastoma immune response induced by anti-GD(2) antibody ch14.18/CHO. Oncoimmunology 2017; 6 (10): e1343775. DOI: 10.1080/2162402X.2017.1343775

75. Ehlert K., Hansjuergens I., Zinke A., Otto S., Siebert N., Henze G., et al. Nivolumab and dinutuximab beta in two patients with refractory neuroblastoma. J Immunother Cancer 2020; 8 (1): e000540. DOI: 10.1136/jitc-2020-000540

76. Wu H.W., Sheard M.A., Malvar J., Fernandez G.E., DeClerck Y.A., Blavier L., et al. Anti-CD105 Antibody Eliminates Tumor Microenvironment Cells and Enhances Anti-GD2 Antibody Immunotherapy of Neuroblastoma with Activated Natural Killer Cells. Clin Cancer Res 2019; 25 (15): 4761– 74. DOI: 10.1158/1078-0432.CCR-18-3358