Combining peptide vaccination with immunostimulatory monoclonal antibodies provides potent immunotherapy in neuroblastoma


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Juliet Gray, Martin Glennie

University of Southampton, UK

Abstract

Neuroblastoma is one of the commonest extra-cranial tumours of childhood. The majority of children present with metastatic disease for which long term survival remains poor despite intensive multi-modal therapies. Immunotherapy is an attractive new therapeutic approach for these children, holding the possibility of a more specific and less toxic treatment than conventional therapies.

A number of neuroblastoma tumour antigens have been identified. Survivin is particularly promising as an immunotherapy target as it is expressed in 80-100% of high risk tumours and only minimally in normal tissue. Spontaneous anti-survivin T cell responses have been reported, with one study reporting responses in 8 of 9 children with neuroblastoma. Immunostimulatory monoclonal antibodies (mAbs) potentially offer a practical and potent means of boosting these weak endogenous responses to achieve therapeutic immunity. Such mAbs target co-stimulatory molecules (e.g. 4-1BB, OX40, CD40, CTLA-4), providing agonistic or counter-regulatory signals. They have already shown promise in adult clinical trial in a number of different malignancies. There is, as yet, no clinical experience in paediatric patients.

Here we demonstrate the efficacy of immunostimulatory mAbs in murine syngeneic neuroblastoma models. In the weakly immunogenic Neuro2a neuroblastoma model, treatment of established subcutaneous tumour with either anti-4-1BB, anti-CD40 or anti-CTLA-4 mAb results in resolution of tumour and long-term survival in 40-60% of mice. This is dependent on NK and CD8+ T cells and a tumour CD8+ lymphocyte infiltrate is observed. Therapy is only achieved if mAb is given to mice once tumours are established, suggesting that it is dependent on the presence of antigen from the tumour. In the aggressive, poorly immunogenic AgN2a and NXS2 neuroblastoma models, single agent immunostimulatory mAb therapy results in only marginal slowing of tumour growth. However if mAb (anti-CTLA-4) is given in conjunction with survivin peptide vaccination then 60% long term survival is achieved. Surviving mice have persisting (> 90 days) T-cell immunity to survivin as demonstrated by intracellular interferon-γ staining. This data suggests the combination of antigen and co-stimulatory mAb may provide effective immunotherapy against neuroblastoma.