Entire world going nuts about IL-2 mimetics (THOR et al.), while "toxicity-modified" anti-CD40 gets no respect.....
J Immunother Cancer. 2019 Dec 6;7(1):344. doi: 10.1186/s40425-019-0823-6.
Combined innate and adaptive immunotherapy overcomes resistance of immunologically cold syngeneic murine neuroblastoma to checkpoint inhibition.
Voeller J1, Erbe AK2, Slowinski J2, Rasmussen K2, Carlson PM2, Hoefges A2, VandenHeuvel S2, Stuckwisch A2, Wang X3, Gillies SD4, Patel RB2, Farrel A5, Rokita JL5, Maris J5, Hank JA2, Morris ZS2, Rakhmilevich AL2, Sondel PM1,2.
1
Department of Pediatrics, University of Wisconsin, 4159 WIMR Bldg., UWCCC, 1111 Highland Ave, Madison, WI, 53711, USA.
2
Department of Human Oncology, University of Wisconsin, 4159 WIMR Bldg., UWCCC, 1111 Highland Ave, Madison, WI, 53711, USA.
3
Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison, WI, USA.
4
Provenance Biopharmaceuticals, Carlisle, MA, USA.
5
Children's Hospital of Philadelphia, Philadelphia, PA, USA.
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. |
