Immunomodulatory monoclonal antibodies combined with peptide vaccination provide potent immunotherapy in an aggressive murine neuroblastoma model

Emily L Williams, Stuart N Dunn, Sonya James, Peter W Johnson, Mark S Cragg, Martin J Glennie, Juliet C Gray

Research output: Contribution to journalArticle (Academic Journal)peer-review

32 Citations (Scopus)

Abstract

PURPOSE: 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.

EXPERIMENTAL DESIGN: 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.

Original languageEnglish
Pages (from-to)3545-55
Number of pages11
JournalClinical Cancer Research
Volume19
Issue number13
DOIs
Publication statusPublished - 1 Jul 2013

Keywords

  • Amino Acid Sequence
  • Animals
  • Antibodies, Monoclonal
  • Antigens, CD40
  • CD8-Positive T-Lymphocytes
  • CTLA-4 Antigen
  • Cancer Vaccines
  • Cell Line, Tumor
  • Disease Models, Animal
  • Disease Progression
  • Humans
  • Immunomodulation
  • Immunotherapy
  • Killer Cells, Natural
  • Mice
  • Neuroblastoma
  • Spleen
  • Vaccines, Subunit

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