Cancer Immunology, Immunotherapy

, Volume 57, Issue 11, pp 1625–1634

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

  • Michela Croce
  • Raffaella Meazza
  • Anna M. Orengo
  • Marina Fabbi
  • Martina Borghi
  • Domenico Ribatti
  • Beatrice Nico
  • Barbara Carlini
  • Vito Pistoia
  • Maria Valeria Corrias
  • Silvano Ferrini
Original Article

DOI: 10.1007/s00262-008-0496-3

Cite this article as:
Croce, M., Meazza, R., Orengo, A.M. et al. Cancer Immunol Immunother (2008) 57: 1625. doi:10.1007/s00262-008-0496-3
  • 147 Downloads

Abstract

Aim

IL-21 is the most recently identified member of the IL-2 cytokine family. Here we studied the therapeutic efficacy of IL-21-gene-modified cells (Neuro2a/IL-21) in a syngeneic metastatic neuroblastoma (NB) model.

Materials and methods

Neuro2a/IL-21 cells were tested as subcutaneous (sc) vaccine both in prophylactic and therapeutic settings. Depletion studies, cytotoxicity assay and immunohistochemical analyses were carried out to evaluate the mechanisms involved in tumor rejection.

Results

When injected sc in syngeneic A/J mice viable Neuro2a/IL-21 cells were rejected and induced resistance to a subsequent iv challenge with Neuro2a parental cells (Neuro2a/pc), suggesting the involvement of an immune response. More importantly, in mice bearing Neuro2a/pc micrometastases, a single sc injection of Neuro2a/IL-21 cells significantly increased the mean tumor-free survival of treated animals (43 vs. 22 days) and cured 14% of them. The administration of two or three doses of Neuro2a/IL-21 cell vaccine further increased the mean survival time to 54 and 75 days, and the cure rate to 27 and 33%, respectively, whereas the use of unmodified Neuro2a or mock-transfected cells had no effect. In vivo cell subset depletion and a Winn-assay indicated the involvement of CD8 + CTLs. Immunohistochemical analysis indicated a reduction of CD31+ and VEGFR2+ microvessels in late metastases from therapeutically vaccinated mice. A role of survivin as antigen was suggested by in vitro assays using survivin-synthetic CTL-epitopes.

Conclusions

Our present data indicate that IL-21-secreting NB cells are effective as therapeutic vaccine in mice bearing metastatic NB, through a specific CTL response involving survivin as antigen, and suggest a potential interest for IL-21 in NB immuno-gene therapy.

Keywords

SurvivinCancer vaccineInterleukin-21Neuroblastoma

Supplementary material

262_2008_496_MOESM1_ESM.pdf (582 kb)
(PDF 582 kb)

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Michela Croce
    • 1
  • Raffaella Meazza
    • 2
  • Anna M. Orengo
    • 1
  • Marina Fabbi
    • 1
  • Martina Borghi
    • 1
  • Domenico Ribatti
    • 4
  • Beatrice Nico
    • 4
  • Barbara Carlini
    • 3
  • Vito Pistoia
    • 3
  • Maria Valeria Corrias
    • 3
  • Silvano Ferrini
    • 1
  1. 1.Laboratory of Immunological TherapyIstituto Nazionale per la Ricerca sul CancroGenoaItaly
  2. 2.Laboratory of Clinical and Experimental ImmunologyGaslini InstituteGenoaItaly
  3. 3.Laboratory of OncologyGaslini InstituteGenoaItaly
  4. 4.Department of Human AnatomyPoliclinicoBariItaly