Combined innate and adaptive immunotherapy overcomes resistance of immunologically cold syngeneic murine neuroblastoma to checkpoint inhibition

Autor: Anna Hoefges, Julie Voeller, Sabrina VandenHeuvel, John M. Maris, Peter M. Carlson, Jacquelyn A. Hank, Amy K. Erbe, Kayla Rasmussen, Jacob Slowinski, Xing Wang, Jo Lynne Rokita, Paul M. Sondel, Alexander L. Rakhmilevich, Alvin Farrel, Ravi Patel, Stephen D. Gillies, Ashley Stuckwisch, Zachary S. Morris
Jazyk: angličtina
Rok vydání: 2019
Předmět:
0301 basic medicine
Cancer Research
Pediatric cancer
medicine.medical_treatment
Cell
Combination immunotherapy
Adaptive Immunity
Anti-disialogangliodside (anti-GD2)
Neuroblastoma
Mice
0302 clinical medicine
Antineoplastic Agents
Immunological
Tumor Cells
Cultured
Tumor Microenvironment
Immunology and Allergy
Radiation
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Immunohistochemistry
3. Good health
medicine.anatomical_structure
Oncology
030220 oncology & carcinogenesis
Molecular Medicine
Cytokines
Female
Research Article
medicine.drug_class
Immunologically cold tumors
Immunology
Monoclonal antibody
lcsh:RC254-282
03 medical and health sciences
Immune system
Checkpoint blockade
Cell Line
Tumor
medicine
Biomarkers
Tumor
Animals
Pharmacology
Tumor microenvironment
Innate immune system
business.industry
Immunotherapy
medicine.disease
Immunity
Innate
Disease Models
Animal
030104 developmental biology
Drug Resistance
Neoplasm
Cancer research
business
Immunologic Memory
Zdroj: Journal for Immunotherapy of Cancer
Journal for ImmunoTherapy of Cancer, Vol 7, Iss 1, Pp 1-13 (2019)
ISSN: 2051-1426
Popis: 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.
Databáze: OpenAIRE
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