Abstract
BackgroundUnlike some adult cancers, most pediatric cancers are considered immunologically cold and generally less responsive to immunotherapy. While immunotherapy has already been incorporated into standard of care treatment for pediatric patients with high-risk neuroblastoma, overall survival remains poor. In a mouse melanoma model, we found that radiation and tumor-specific immunocytokine generate an in situ vaccination response in syngeneic mice bearing large tumors. Here, we tested whether a novel immunotherapeutic approach utilizing radiation and immunocytokine together with innate immune stimulation could generate a potent antitumor response with immunologic memory against syngeneic murine neuroblastoma.MethodsMice bearing disialoganglioside (GD2)-expressing neuroblastoma tumors (either NXS2 or 9464D-GD2) were treated with radiation and immunotherapy (including anti-GD2 immunocytokine with or without anti-CTLA-4, CpG and anti-CD40 monoclonal antibody). Tumor growth, animal survival and immune cell infiltrate were analyzed in the tumor microenvironment in response to various treatment regimens.ResultsNXS2 had a moderate tumor mutation burden (TMB) while N-MYC driven 9464D-GD2 had a low TMB, therefore the latter served as a better model for high-risk neuroblastoma (an immunologically cold tumor). Radiation and immunocytokine induced a potent in situ vaccination response against NXS2 tumors, but not in the 9464D-GD2 tumor model. Addition of checkpoint blockade with anti-CTLA-4 was not effective alone against 9464D-GD2 tumors; inclusion of CpG and anti-CD40 achieved a potent antitumor response with decreased T regulatory cells within the tumors and induction of immunologic memory.ConclusionsThese data suggest that a combined innate and adaptive immunotherapeutic approach can be effective against immunologically cold syngeneic murine neuroblastoma. Further testing is needed to determine how these concepts might translate into development of more effective immunotherapeutic approaches for the treatment of clinically high-risk neuroblastoma.
Highlights
Neuroblastoma is the most common extracranial solid tumor in pediatrics
We previously demonstrated that local external beam radiation therapy (RT) and intratumoral (IT) injection of the hu14.18-IL2 immunocytokine (IC), a fusion protein linking hu14.18 anti-GD2 monoclonal antibody (mAb) and IL2, achieves improved tumor control and survival in mice bearing B78 melanoma, which expresses GD2 [10, 11]
We previously showed that injection of IC (IT-IC), with or without RT and anti-CTLA-4, can serve as an in situ vaccination, enhancing local antitumor effects and generating a systemic adaptive T cell response against distant tumors [10]
Summary
Neuroblastoma is the most common extracranial solid tumor in pediatrics. Overall survival is poor for highrisk cases and accounts for about 15% of childhood cancer-related mortality [1,2,3]. Our prior preclinical work investigating immunotherapy regimens using a tumor-specific monoclonal antibody (mAb) [anti-disialoganglioside (GD2), referred to as “anti-GD2”] together with an immunostimulatory agent [interleukin-2 (IL2)] has already been successfully translated to the clinical setting, which has significantly improved survival for patients with high-risk disease [4]. Current standard of care treatment for patients with high-risk neuroblastoma includes multi-agent chemotherapy, surgical resection, autologous stem cell transplantation, radiation therapy and immunotherapy [with anti-GD2 mAb, granulocyte-macrophage colonystimulating factor (GM-CSF), IL2 and retinoic acid]. Enhancing the current immunotherapy may play a role in further improving survival for these patients by enabling tumor-selective killing with minimal harm to normal tissues, achieving cures via eradicating all disease sites, generating immune memory and potentially reducing reliance on genotoxic high-dose chemoradiation. While immunotherapy has already been incorporated into standard of care treatment for pediatric patients with high-risk neuroblastoma, overall survival remains poor. We tested whether a novel immunotherapeutic approach utilizing radiation and immunocytokine together with innate immune stimulation could generate a potent antitumor response with immunologic memory against syngeneic murine neuroblastoma
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