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Antibody-based immunotherapy in high-risk neuroblastoma

  • Erik Johnson (a1), Shannon M. Dean (a2) and Paul M. Sondel (a3)

Although great advances have been made in the treatment of low- and intermediate-risk neuroblastoma in recent years, the prognosis for advanced disease remains poor. Therapies based on monoclonal antibodies that specifically target tumour cells have shown promise for treatment of high-risk neuroblastoma. This article reviews the use of monoclonal antibodies either as monotherapy or as part of a multifaceted treatment approach for advanced neuroblastoma, and explains how toxins, cytokines, radioactive isotopes or chemotherapeutic drugs can be conjugated to antibodies to enhance their effects. Tumour resistance, the development of blocking antibodies, and other problems hindering the effectiveness of monoclonal antibodies are also discussed. Future therapies under investigation in the area of immunotherapy for neuroblastoma are considered.

Corresponding author
*Corresponding author: Paul M. Sondel, Departments of Pediatrics, Human Oncology and Genetics and University of Wisconsin Paul P. Carbone Cancer Center, The University of Wisconsin-Madison, K4/448 600 Highland Avenue, Madison, WI 53792, USA. Tel: +1 608 263 9069; Fax: +1 608 263 4226; E-mail:
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1 N.K. Cheung , B.H. Kushner and K. Kramer (2001) Monoclonal antibody-based therapy of neuroblastoma. Hematol Oncol Clin North Am 15, 853-866

6 K.K. Matthay (1999) Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. N Engl J Med 341,1165-1173

7 F. Berthold (2005) Myeloablative megatherapy with autologous stem cell resuce versus oral maintenance chemotherapy as consolidation treatment in patients with high-risk neuroblastoma: a randomized controlled trial. Lancet Oncol 6, 649-658

8 L.M. Franks (1997) Neuroblastoma in adults and adolescents: An indolent course with poor survival. Cancer 79, 2028-2035

9 P.M. Sondel and J.A. Hank (2001) Antibody-directed, effector cell-mediated tumor destruction. Hematol Oncol Clin North Am 15, 703-721

10 J. Stephenson (1995) Reengineered mononclonal antibodies step up to the plate in cancer studies. JAMA 274, 1821-1822

13 T.J. Moss (1991) Prognostic value of immunocytologic detection of bone marrow metastases in neuroblastoma. N Engl J Med 324, 219-226

15 F. Colucci , M.A. Caligiuri and J.P. Santo (2003) What does it take to make a natural killer cell? Nat Rev Immunol 3, 413-425

16 N.K. Cheung and P.M. Sondel (2005) Neuroblastoma immunology and immunotherapy. In Neuroblastoma ( S. Cohn and N.K. Cheung , eds), pp. 223-242, Springer Press

19 L. Svennerholm (1994) Gangliosides and allied glycosphingolipids in human peripheral nerve and spinal cord. Biochem Biophys Acta 1214, 115-123

23 B.H. Kushner (2002) Curability of recurrent disseminated disease after surgery alone for local-regional neuroblastoma using intensive chemotherapy and anti-GD2 immunotherapy. J Pediatr Hematol Oncol 25, 515-519

28 N.K. Cheung (2000) Monoclonal antibody-based therapy for neuroblastoma. Curr Oncol Rep 2(6), 547-553

29 I.Y. Cheung (2003) Early molecular response in marrow is highly prognostic following treatment with anti-GD2 and GM-CSF. JCO 21, 3853-3858

30 I.Y. Chueng (2003) Quantitations of GD2 synthase mRNA by real time reverse transcriptase polymerase chain reaction: clinical utility in evaluating adjuvant therapy in neuroblastoma. J Clin Oncol 21, 1087-1093

32 W.H. Xiao , A. Yu and L.S. Sorkin (1997) Electrophysiological characteristics of primary afferent fibers after systemic administration of anti-GD2 ganglioside antibody. Pain 69, 145-151

33 N. Yuki (1997) Pathogenesis of the neurotoxicity caused by anti-GD antibody therapy. J Neurol Sci 149, 127-130

35 N.K. Cheung (1988) Decay-accelerating factor protects human tumor cells from compelement-mediated cytotoxicity in vitro. J Clin Invest 81, 1122-1128

37 S. Chen (2000) Surface antigen expression and complement susceptibility of differentiated neuroblastoma clones. Am J Pathol 156, 1085-1091

42 R. Handgretinger (1992) A Phase I study of neuroblastoma with the anti-ganglioside GD2 antibody 14.G2a. Cancer Immunol Immunother 35, 199-204

47 M.M. Uttenreuther-Fischer , C.S. Huang and A.L. Yu (1995) Pharmacokinetics of human-mouse chimeric anti-GD2 mAb ch14.18 in a phase I trial in neuroblastoma patients. Cancer Immunol Immunother 41, 331-338

51 G.C. Baldwin (1993) Colony stimulating factor enhancement of myeloid effector cell cytotoxicity towards neuroectodermal tumor cells. Br J Haematol 83, 545-553

54 J.D. Frost (1997) A Phase I/IB trial of murine monoclonal anti-GD2 antibody 14.G2a plus Interleukin-2 in children with refractory neuroblastoma: a report of the Children's Cancer Group. Cancer 80, 317-333

59 J.A. Hank (1994) Treatment of neuroblastoma patients with antiganglioside GD2 antibody plus interleukin-2 induces antibody dependent cellular cytotoxicity against neuroblastoma detected in vitro. J Immunother 15, 29-37

63 V. Vetvicka , B.P. Thornton and G.D. Ross (1996) Soluble β-glucan polysaccharide binding to the lectin site of neutrophil or natural killer cell complement receptor type 3 (CD11b/CD18) generates a primed state of the receptor capable of mediating cytotoxicity of iC3b-opsonized target cells. J Clin Invest 98, 50-61

66 F. Hong (2004) Mechanism by which orally administered B-1,3-glucans enhance the tumoricidal activity of antitumor monoclonal antibodies in murine tumor models. J Immunol 173, 797-806

68 O. Manzke (2001) Immunotherapeutic strategies in neuroblastoma: antitumoral activity of deglycosylated ricin A conjugated anti-GD2 antibodies and anti-CD3xanti-GD2 bispecific antibodies. Med Pediatr Oncol 36, 185-189

70 P.B. Thomas (2002) Effective targeted cytotoxicity of neuroblastoma Cells. J Pediatr Surg 37, 539-544

71 H. Juhl (1997) Additive cytotoxicity of different monoclonal antibody-cobra venom factor conjugates for human neuroblastoma cells. Immunobiology 197, 444-459

72 U. Holzer (1995) Superantigen-staphylococcal-enterotoxin A-dependent and antibody-targeted lysis of GD2-positive neuroblastoma cells. Cancer Immunol Immunother 41, 129-136

74 L. Raffaghello (2003) In vitro and in vivo antitumor activity of liposomal fenretinide targeted to human neuroblastoma. Int J Cancer 104, 559-567

75 P. Reuland (2001) Follow-up in neuroblastoma: comparison of metaiodobenzylguanidine and a chimeric anti-GD2 antibody for detection of tumor relapse and therapy response. J Pediatr Hematol Oncol 23, 437-444

76 A. Goldman (1984) Immunolocalization of neuroblastoma using radiolabeled monoclonal antibody UJ13A. J Pediatr 105, 252-256

77 F. Berthold (1990) Immunoscintigraphic imaging of mIBG-negative metastases in neuroblastoma. Am J Pediatr Hematol Oncol 12, 61-62

78 F. Carrel (1997) Evaluation of radioiodinated and radiocopper labeled monovalent fragments of monoclonal antibody chCE7 for targeting of neuroblastoma. Nucl Med Biol 24, 539-546

80 N.K. Cheung (2001) N7: a novel multi-modality therapy of high-risk neuroblastoma in children diagnosed over 1 year of age. Med Pediatr Oncol 36, 227-230

81 K. Kramer (2001) Neuroblastoma metastatic to the central nervous system: The Memorial Sloan-Kettering Cancer Center experience and a literature review. Cancer 91, 1510-1519

83 I. Bergman (1999) Intrathecal administration of an antiganglioside antibody results in specific accumulation within meningeal neoplastic xenografts in nude rats. J Immunother 22, 114-123

84 K. Kramer (2000) Targeted radioimmunotherapy for leptomeningeal cancer using I131-3F8. Med Pediatr Oncol 35, 716-718

86 H.N. Lode (1998) Immunocytokines: a promising approach to cancer immunotherapy. Pharmacol Ther 80, 277-292

87 S.D. Gillies (1993) Biological activity and in vivo clearance of antitumor antibody/cytokine fusion proteins. Bioconjugate Chem 4, 230-235

89 S.D. Gillies (1992) Antibody-targeted interleukin 2 stimulates the T-cell killing of autologous tumor cells. Proc Natl Acad Sci U S A 89, 1428-1432

91 S.D. Voss (1990) Increased expression of the interleukin 2 (IL2) receptor beta chain (p70) on CD56+ natural killer cells after in vivo IL2 therapy: p70 expression does not alone predict the level of intermediate affinity IL2 binding. J Exp Med 172, 1101-1114

93 H.N. Lode (1997) Targeted interleukin-2 therapy of spontaneous neuroblastoma metastases to bone marrow. J Natl Cancer Inst 89, 1586-1594

95 K.L. Osenga (2006) A Phase I clinical trial of 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 12, 1750-1759

97 T. Klingebiel (1998) Treatment of neuroblastoma stage 4 with 131I-meta-iodo-benzylguanidine, high dose chemotherapy and immunotherapy: A pilot study. Eur J Cancer 34, 1398-1402

98 T. Simon (2004) Consolidation treatment with chimeric anti-GD2-antibody ch14.18 in children older than 1 year with metastatic neuroblastoma. J Clin Oncol 22, 3549-3557

99 T. Simon (2005) Infants with stage 4 neuroblastoma: the impact of the chimeric anti-GD2-antibody ch14.18 consolidation therapy. Klin Padiatr 217(3), 147-152

100 B.K. Kushner (2004) Camptothecin Analogs (Irinotecan or Topotecan) plus high-dose cyclophosphamide as preparative regimens for antibody-based immunotherapy in resistant neuroblastoma. Clin Canc Res 10, 84-87

102 A.M. Yeager (1986) Autologous bone marrow transplantation in patients with acute nonlymphocytic leukemia using ex vivo marrow treatment with 4-hydroperoxycyclophosphamide. N Engl J Med 315, 141-147

106 I.Y. Cheung (2002) Quantitation of GD2 synthase mRNA by real-time reverse transcription-polymerase chain reaction: utility in bone marrow purging of neuroblastoma by anti-GD2 antibody 3F8. Cancer 94, 3042-3048

107 J. Donovan (2000) CD34 selection as a stem cell purging strategy for neuroblastoma: preclinical and clinical studies. Med Pediatr Oncol 35, 677-682

108 R. Handgretinger (2003) Tumour cell contamination of autologous stem cell grafts in high-risk neuroblastoma: the good news? Br J Cancer 88, 1874-1877

109 Z.C. Neal (2004) NXS2 murine neuroblastomas express increased levels of MHC class I antigens upon recurrence following NK-dependent immunotherapy. Cancer Immunol Immunother 53, 41-52

111 Z.C. Neal (2007) Flt3-L gene therapy enhances immunocytokine-mediated antitumor effects and induces long-term memory. Cancer Immunol Immunother 56, 1765-1774

112 G.V. Shurin (1998) Apoptosis induced in T cells by human neuroblastoma cells: role of Fas ligand. Nat Immun 16(5–6), 263-274

113 A. Gorter and S. Meri (1999) Immune evasion of tumor cells using membrane-bound complement regulatory proteins. Immunol Today 20, 576-582

114 W. Shen and S. Ladisch (2002) Ganglioside GD1a impedes lipopolysaccharide-induced maturation of human dendritic cells. Cell Immunol 220, 125-133

115 S. Caldwell (2003) Mechanisms of ganglioside inhibition of APC function. J Immunol 171, 1676-1683

120 W. Luo (2006) Targeting melanoma cells with human high molecular weight-melanoma associated antigen-specific antibodies elicited by a peptide mimotope: functional effects. J Immunol 176, 6046-6054

121 S. Fest (2006) Characterization of GD2 peptide mimotope DNA vaccines effective against spontaneous neuroblastoma metastases. Cancer Res 66, 10567-10575

122 C.M. Coughlin (2004) RNA-transfected CD40-activated B cells induce functional T-cell responses against viral and tumor antigen targets: implications for pediatric immunotherapy. Blood 103, 20462054

123 C. Rossig and M.K. Brenner (2004) Genetic modification of T lymphocytes for adoptive immunotherapy. Mol Ther 10, 5-18

124 C. Rossig (2001) Targeting of GD2-positive tumor cells by human T lymphoctyes engineered to express chimeric T-cell receptor genes. Int J Cancer 94, 228-236

125 S. Gonzalez (2004) Genetic engineering of cytotoxic T lymphocytes for adoptive T-cell therapy of neuroblastoma. J Gene Med 6, 704-711

127 M.C. Jensen (2000) Human T lymphocyte genetic modification with naked DNA. Mol Ther 1, 49-55

128 L.M. Serrano (2006) Differentiation of naïve cord-blood T cells into CD19-specific cytolytic effectors for post-transplantation adoptive immunotherapy. Blood 107, 2643-2652

129 L.J. Cooper (2006) Manufacturing of gene-modified cytotoxic T lymphocytes for autologous cellular therapy for lymphoma. Cytotherapy 8, 105-117

130 B. Savoldo (2007) Epstein Barr virus-specific cytotoxic T lymphocytes expressing the anti-CD30δ artificial chimeric T-cell receptor for immunotherapy of Hodgkins disease. Blood 110, 2620-2630

131 M.A. Pule (2005) A chimeric T cell antigen receptor that augments cytokine release and supports clonal expansion of primary human T cells. Mol Ther 12, 933-941

132 M. Ferrarini (2002) Human gammadelta T cells: a nonredundant system in the immune-surveillance against cancer. Trends Immunol 23, 14-28

134 M. Otto (2005) Combination immunotherapy with clinical-scale enriched human γδ T cells, hu14.18 antibody, and the immunocytokine Fc-IL7 in disseminated neuroblastoma. Clin Cancer Res 11, 8486-8491

135 H.A. Whittington , J. Hancock and J.T. Kemshead (2001) Generation of humanized single chain Fv (Scfv) derived from the monoclonal ERIC-1 recognizing the human neural cell adhesion molecule. Med Pediatr Oncol 36, 243-246

139 S. Siberil (2007) FcγR: The key to optimize therapeutic antibodies? Crit Rev Oncol Hematol 62, 26-33

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