title: Immunomodulatory monoclonal antibodies combined with peptide vaccination provide potent immunotherapy in an aggressive murine neuroblastoma model.
abstract: OBJECTIVE
  Neuroblastoma is one of the commonest extracranial tumors of childhood. The majority of patients present with metastatic disease for which outcome remains poor. Immunotherapy is an attractive therapeutic approach for this disease, and a number of neuroblastoma tumor antigens have been identified. Here, we examine the therapeutic potential of combining immunomodulatory monoclonal antibodies (mAb) with peptide vaccination in murine neuroblastoma models.
  
  
  METHODS
  Neuroblastoma-bearing mice were treated with mAb targeting 4-1BB, CD40, and CTLA-4 alone, or in combination with a peptide derived from the tumor antigen survivin (GWEDPPNDI). Survivin-specific immune response and therapeutic efficacy were assessed.
  
  
  RESULTS
  In the Neuro2a model, treatment of established tumor with anti-4-1BB, anti-CD40, or anti-CTLA-4 mAb results in tumor regression and long-term survival in 40% to 60% of mice. This is dependent on natural killer (NK) and CD8(+) T cells and is associated with tumor CD8(+) lymphocyte infiltrate. Successful therapy is achieved only if mAb is given to mice once tumors are established, suggesting dependence on sufficient tumor to provide antigen. In the more aggressive AgN2a and NXS2 models, single-agent mAb therapy provides ineffective therapy. However, if mAb (anti-CTLA-4) is given in conjunction with survivin peptide vaccination, then 60% long-term survival is achieved. This is associated with the generation of survivin-specific T-cell immunity, which again is only shown in the presence of tumor antigen.
  
  
  CONCLUSIONS
  These data suggest that the combination of antigen and costimulatory mAb may provide effective immunotherapy against neuroblastoma and may be of particular use in the minimal residual disease setting.
authors: Antibody and Vaccine Group, Cancer Research UK Experimental Cancer Medicine Centre, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
authors: Emily L
authors: EL
authors: Williams
authors: Stuart N
authors: SN
authors: Dunn
authors: Sonya
authors: S
authors: James
authors: Peter W
authors: PW
authors: Johnson
authors: Mark S
authors: MS
authors: Cragg
authors: Martin J
authors: MJ
authors: Glennie
authors: Juliet C
authors: JC
authors: Gray
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D019013:CD40 Antigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D060908:CTLA-4 Antigen / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D056747:Immunomodulation / Q000187:drug effects* / Q000276:immunology*; D007167:Immunotherapy; D007694:Killer Cells, Natural / Q000276:immunology; D051379:Mice; D009447:Neuroblastoma / Q000276:immunology* / Q000401:mortality / Q000628:therapy*; D013154:Spleen / Q000166:cytology / Q000276:immunology; D022223:Vaccines, Subunit
chemical_list: D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D060908:CTLA-4 Antigen; D019496:Cancer Vaccines; D022223:Vaccines, Subunit
references: Clin Exp Immunol. 2009 Jul;157(1):9-19
references: 19659765
references: Cancer Res. 2003 Sep 1;63(17):5480-9
references: 14500384
references: J Immunol. 2008 Oct 1;181(7):4621-31
references: 18802064
references: Pediatr Blood Cancer. 2008 Dec;51(6):747-53
references: 18704922
references: Cancer Invest. 2007 Feb;25(1):67-77
references: 17364560
references: Hybridoma. 1991 Apr;10(2):219-27
references: 1908435
references: Immunol Rev. 2003 Apr;192:161-80
references: 12670403
references: Immunol Cell Biol. 2005 Aug;83(4):344-51
references: 16033529
references: J Pediatr Surg. 1968 Feb;3(1):161-4
references: 5655566
references: Clin Cancer Res. 2009 Oct 15;15(20):6446-53
references: 19808874
references: Cancer Sci. 2011 Feb;102(2):324-9
references: 21143701
references: J Clin Invest. 2002 Mar;109(5):651-9
references: 11877473
references: Biochem J. 2010 Sep 1;430(2):199-205
references: 20704571
references: Cancer Immunol Immunother. 2008 Nov;57(11):1625-34
references: 18324400
references: Int J Cancer. 2009 Jul 1;125(1):104-14
references: 19291796
references: N Engl J Med. 2010 Aug 19;363(8):711-23
references: 20525992
references: Eur J Immunol. 2002 Dec;32(12):3617-27
references: 12516549
references: J Clin Invest. 2010 Nov;120(11):3869-77
references: 20978348
references: J Immunother. 2007 Feb-Mar;30(2):227-33
references: 17471169
references: J Immunol. 2002 Mar 15;168(6):2720-8
references: 11884438
references: Update Cancer Ther. 2007 Jun 1;2(2):61-65
references: 19587842
references: J Immunol. 1998 Sep 15;161(6):3176-85
references: 9743386
references: Curr Mol Med. 2009 Aug;9(6):683-93
references: 19689295
references: Lancet Oncol. 2008 Mar;9(3):247-56
references: 18308250
references: J Pediatr Surg. 2005 Jan;40(1):244-9; discussion 249-50
references: 15868592
references: J Clin Oncol. 2009 Sep 10;27(26):4371-7
references: 19636010
references: Curr Opin Immunol. 2004 Jun;16(3):321-7
references: 15134781
references: J Immunol. 2002 Aug 15;169(4):1792-800
references: 12165501
references: Semin Oncol. 2010 Oct;37(5):460-7
references: 21074061
references: Br J Cancer. 2003 May 19;88(10):1527-36
references: 12771917
references: Ann Surg Oncol. 2005 Dec;12(12):1005-16
references: 16283570
references: Cancer Immunol Immunother. 2009 Nov;58(11):1801-7
references: 19294381
references: Br J Cancer. 1972 Aug;26(4):321-30
references: 5071193
references: Ann N Y Acad Sci. 2004 Dec;1028:69-80
references: 15650233
references: Lancet Oncol. 2005 Sep;6(9):649-58
references: 16129365
references: Cancer Lett. 2008 Dec 18;272(2):186-96
references: 18585853
references: Nat Med. 1997 Jun;3(6):682-5
references: 9176498
references: Cancer Immunol Immunother. 2007 Nov;56(11):1733-42
references: 17426969
references: Int J Cancer. 1993 Nov 11;55(5):817-23
references: 8244579
references: Semin Oncol. 2010 Oct;37(5):430-9
references: 21074057
references: N Engl J Med. 2010 Sep 30;363(14):1324-34
references: 20879881
references: Blood. 1998 Mar 1;91(5):1706-15
references: 9473237
references: Cancer Res. 2005 Feb 1;65(3):1089-96
references: 15705911
references: Eur J Immunol. 1994 Aug;24(8):1835-42
references: 7519998
references: Pediatr Blood Cancer. 2009 Dec;53(6):931-40
references: 19591222
references: Clin Sci (Lond). 2006 Aug;111(2):93-106
references: 16831129
references: Cancer Immunol Immunother. 2005 Apr;54(4):400-6
references: 15449039
references: J Clin Oncol. 2006 Dec 20;24(36):5725-34
references: 17179106
references: Eur J Immunol. 1990 Dec;20(12):2747-55
references: 1980112
references: Science. 1996 Mar 22;271(5256):1734-6
references: 8596936