Abstract
Interleukin (IL)-21, the lastly discovered member of the IL-2 family, is a pleiotropic cytokine produced by CD4+ T cells. IL-21 has shown anti-tumour activity in several pre-clinical tumour models. In addition, clinical phase I-II trials have shown that IL-21 has an acceptable toxicity and induces immune-activation resulting in some clinical responses in patients with metastatic melanoma and renal carcinoma. Stage 4 neuroblastoma (NB) is frequently an incurable disease and it is assumed that immunotherapy (IT) may complement existing treatments. We developed a syngeneic mouse model of Neuro2a NB resembling human stage 4 disease to test different therapies. IT with a cellular vaccine consisting of IL-21-transduced NB cells (Neuro2a/IL-21) cured about one third of syngeneic mice bearing disseminated NB, through a CD8+ T cell-dependent response. NB may induce immune-regulatory mechanisms, which may limit the efficacy of IT. The co-administration of an anti-CD25 monoclonal antibody (mAb), targeting immune-suppressive CD4+CD25+FoxP3+ regulatory T (Treg) cells, slightly augmented the efficacy of IL-21-based IT. However, an anti-CD4 mAb combined with the vaccine produced an even higher cure rate (80%). The potent synergistic effect achieved by the anti-CD4 mAb was related to a complete depletion of CD4+CD25+FoxP3+ Treg cells and possibly of other tumour-conditioned CD4+ T cell subsets. Mice receiving the IL-21-releasing vaccine+anti-CD4 mAb recovered their CD4+ T cell counts in 90 days and developed immunity to NB. Preliminary data indicate that the administration of recombinant (r) IL-21 may have limited effects but that anti-CD4 mAb co-treatment strongly augmented IL-21 IT. These data open new perspectives for the use of IL-21-based immunotherapy in conjunction with CD4+ lymphodepletion in human stage 4 NB.
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Acknowledgements
This study was supported in part by Italian Neuroblastoma Foundation, AIRC (Italian Association for Cancer Research) and Italian Ministry of Health. MC is recipient of fellowships awarded by the Italian Neuroblastoma Foundation.
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Croce, M., Corrias, M.V., Ferrini, S. (2012). Neuroblastoma: Perspectives for the Use of IL-21 in Immunotherapy. In: Hayat, M. (eds) Neuroblastoma. Pediatric Cancer, vol 1. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-2418-1_12
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