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Immunotherapy of neuroblastoma by an Interleukin-21-secreting cell vaccine involves survivin as antigen

Michela Croce1, Raffaella Meazza, Anna M Orengo

  • 1Laboratory of Immunological Therapy, Istituto Nazionale per la Ricerca sul Cancro, Largo Benzi 10, 16132 Genoa, Italy.

Cancer Immunology, Immunotherapy : CII
|March 8, 2008
PubMed
Abstract

Insights

Interleukin-21 (IL-21) gene-modified neuroblastoma cells show therapeutic promise. This study demonstrates IL-21 secreting cells effectively treat metastatic neuroblastoma in mice, suggesting potential for immuno-gene therapy.

Area of Science:

  • Immunology
  • Oncology
  • Biotechnology

Background:

  • Interleukin-21 (IL-21) is a recently identified cytokine within the IL-2 family.
  • Neuroblastoma (NB) is a pediatric cancer with significant metastatic potential.
  • Gene-modified cell therapy offers a novel approach to cancer treatment.

Purpose of the Study:

  • To investigate the therapeutic efficacy of IL-21-gene-modified neuroblastoma cells (Neuro2a/IL-21) in a syngeneic metastatic neuroblastoma model.
  • To evaluate the potential of Neuro2a/IL-21 as a therapeutic vaccine for neuroblastoma.
  • To elucidate the immune mechanisms underlying tumor rejection induced by Neuro2a/IL-21 cells.

Main Methods:

  • Neuro2a/IL-21 cells were administered as subcutaneous vaccines in prophylactic and therapeutic settings.
  • Tumor rejection mechanisms were assessed using depletion studies, cytotoxicity assays, and immunohistochemical analyses.
  • In vitro assays using survivin-synthetic CTL-epitopes were performed to identify potential antigens.

Main Results:

  • Subcutaneous injection of viable Neuro2a/IL-21 cells led to their rejection and induced resistance to subsequent tumor challenge, indicating an immune response.
  • In mice with established micrometastases, Neuro2a/IL-21 therapy significantly improved tumor-free survival and achieved a cure rate.
  • Multiple doses of Neuro2a/IL-21 vaccine further enhanced survival rates and cure rates, with no effect observed from unmodified or mock-transfected cells.
  • CD8+ cytotoxic T lymphocytes (CTLs) were implicated in tumor rejection, and immunohistochemistry revealed reduced microvessel density in metastases.
  • Survivin was suggested as a relevant antigen through in vitro assays.

Conclusions:

  • IL-21-secreting neuroblastoma cells demonstrate effectiveness as a therapeutic vaccine in a murine model of metastatic neuroblastoma.
  • The therapeutic effect is mediated by a specific CTL response, with survivin identified as a potential antigen.
  • These findings suggest a promising role for IL-21 in neuroblastoma immuno-gene therapy.

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