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01-05-2014 | Original Article

Recombinant IL-21 and anti-CD4 antibodies cooperate in syngeneic neuroblastoma immunotherapy and mediate long-lasting immunity

Authors: Valentina Rigo, Maria Valeria Corrias, Anna Maria Orengo, Antonella Brizzolara, Laura Emionite, Daniela Fenoglio, Gilberto Filaci, Michela Croce, Silvano Ferrini

Published in: Cancer Immunology, Immunotherapy | Issue 5/2014

Abstract

IL-21 is an immune-enhancing cytokine, which showed promising results in cancer immunotherapy. We previously observed that the administration of anti-CD4 cell-depleting antibody strongly enhanced the anti-tumor effects of an IL-21-engineered neuroblastoma (NB) cell vaccine. Here, we studied the therapeutic effects of a combination of recombinant (r) IL-21 and anti-CD4 monoclonal antibodies (mAb) in a syngeneic model of disseminated NB. Subcutaneous rIL-21 therapy at 0.5 or 1 μg/dose (at days 2, 6, 9, 13 and 15 after NB induction) had a limited effect on NB development. However, coadministration of rIL-21 at the two dose levels and a cell-depleting anti-CD4 mAb cured 28 and 70 % of mice, respectively. Combined immunotherapy was also effective if started 7 days after NB implant, resulting in a 30 % cure rate. Anti-CD4 antibody treatment efficiently depleted CD4⁺ CD25^high Treg cells, but alone had limited impact on NB. Combination immunotherapy by anti-CD4 mAb and rIL-21 induced a CD8⁺ cytotoxic T lymphocyte response, which resulted in tumor eradication and long-lasting immunity. CD4⁺ T cells, which re-populated mice after combination immunotherapy, were required for immunity to NB antigens as indicated by CD4⁺ T cell depletion and re-challenge experiments. In conclusion, these data support a role for regulatory CD4⁺ T cells in a syngeneic NB model and suggest that rIL-21 combined with CD4⁺ T cell depletion reprograms CD4⁺ T cells from immune regulatory to anti-tumor functions. These observations open new perspectives for the use of IL-21-based immunotherapy in conjunction with transient CD4⁺ T cell depletion, in human metastatic NB.

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Title: Recombinant IL-21 and anti-CD4 antibodies cooperate in syngeneic neuroblastoma immunotherapy and mediate long-lasting immunity
Authors: Valentina Rigo
Maria Valeria Corrias
Anna Maria Orengo
Antonella Brizzolara
Laura Emionite
Daniela Fenoglio
Gilberto Filaci
Michela Croce
Silvano Ferrini
Publication date: 01-05-2014
Publisher: Springer Berlin Heidelberg
Published in: Cancer Immunology, Immunotherapy / Issue 5/2014
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-014-1536-9

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