TY - JOUR T1 - Combined innate and adaptive immunotherapy overcomes resistance of immunologically cold syngeneic murine neuroblastoma to checkpoint inhibition JF - Journal for ImmunoTherapy of Cancer JO - J Immunother Cancer DO - 10.1186/s40425-019-0823-6 VL - 7 IS - 1 SP - 344 AU - Julie Voeller AU - Amy K. Erbe AU - Jacob Slowinski AU - Kayla Rasmussen AU - Peter M. Carlson AU - Anna Hoefges AU - Sabrina VandenHeuvel AU - Ashley Stuckwisch AU - Xing Wang AU - Stephen D. Gillies AU - Ravi B. Patel AU - Alvin Farrel AU - Jo Lynne Rokita AU - John Maris AU - Jacquelyn A. Hank AU - Zachary S. Morris AU - Alexander L. Rakhmilevich AU - Paul M. Sondel Y1 - 2019/12/01 UR - http://jitc.bmj.com/content/7/1/344.abstract N2 - Background Unlike 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.Methods Mice 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.Results NXS2 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.Conclusions These 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.Abbreviations:ADCCAntibody-dependent cell-mediated cytotoxicityanti-CTLA-4 or CTLAAnti-cytotoxic T-lymphocyte-associated protein 4anti-PD-L1Anti-programmed cell death protein 1 ligand 1 mAbCRComplete responseGD2DisialogangliosideICImmunocytokineIL2Interleukin-2ITIntratumoralJAXThe Jackson LaboratorymAbMonoclonal antibodyNKNatural killerRTRadiation therapySEMStandard error of meanTACTaconic FarmsTMBTumor mutation burdenTregsT regulatory cellsWESWhole exome sequencing ER -