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

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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.

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Acknowledgments

This work was supported by grants awarded by AIRC, Italian Ministry of Health, Italian Neuroblastoma Foundation and CIPE. MC and BC are recipients of fellowships awarded by Italian Neuroblastoma Foundation. The excellent secretarial support of Ms C Bernardini is deeply acknowledged.

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Authors and Affiliations

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

    Michela Croce, Anna M. Orengo, Marina Fabbi, Martina Borghi & Silvano Ferrini

  2. Laboratory of Clinical and Experimental Immunology, Gaslini Institute, 16147, Genoa, Italy

    Raffaella Meazza

  3. Laboratory of Oncology, Gaslini Institute, 16147, Genoa, Italy

    Barbara Carlini, Vito Pistoia & Maria Valeria Corrias

  4. Department of Human Anatomy, Policlinico, 70124, Bari, Italy

    Domenico Ribatti & Beatrice Nico

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  1. Michela Croce
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  2. Raffaella Meazza
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  4. Marina Fabbi
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  8. Barbara Carlini
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  9. Vito Pistoia
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Corresponding author

Correspondence to Silvano Ferrini.

Additional information

M. V. Corrias and S. Ferrini contributed equally to this work.

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Croce, M., Meazza, R., Orengo, A.M. et al. Immunotherapy of neuroblastoma by an Interleukin-21-secreting cell vaccine involves survivin as antigen. Cancer Immunol Immunother 57, 1625–1634 (2008). https://doi.org/10.1007/s00262-008-0496-3

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  • DOI: https://doi.org/10.1007/s00262-008-0496-3

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