title: Intratumoral IL-12 combined with CTLA-4 blockade elicits T cell-mediated glioma rejection.
abstract: Glioblastomas (GBs) are the most aggressive form of primary brain cancer and virtually incurable. Accumulation of regulatory T (T reg) cells in GBs is thought to contribute to the dampening of antitumor immunity. Using a syngeneic mouse model for GB, we tested whether local delivery of cytokines could render the immunosuppressive GB microenvironment conducive to an antitumor immune response. IL-12 but not IL-23 reversed GB-induced immunosuppression and led to tumor clearance. In contrast to models of skin or lung cancer, IL-12-mediated glioma rejection was T cell dependent and elicited potent immunological memory. To translate these findings into a clinically relevant setting, we allowed for GB progression before initiating therapy. Combined intratumoral IL-12 application with systemic blockade of the co-inhibitory receptor CTLA-4 on T cells led to tumor eradication even at advanced disease stages where monotherapy with either IL-12 or CTLA-4 blockade failed. The combination of IL-12 and CTLA-4 blockade acts predominantly on CD4(+) cells, causing a drastic decrease in FoxP3(+) T reg cells and an increase in effector T (T eff) cells. Our data provide compelling preclinical findings warranting swift translation into clinical trials in GB and represent a promising approach to increase response rates of CTLA-4 blockade in solid tumors.
authors.affiliation: Institute of Experimental Immunology, University of Zurich, 8057 Zurich, Switzerland.
authors.forename: Johannes
authors.initials: J
authors.lastname: Vom Berg
authors.forename: Melissa
authors.initials: M
authors.lastname: Vrohlings
authors.forename: Sergio
authors.initials: S
authors.lastname: Haller
authors.forename: Aladin
authors.initials: A
authors.lastname: Haimovici
authors.forename: Paulina
authors.initials: P
authors.lastname: Kulig
authors.forename: Anna
authors.initials: A
authors.lastname: Sledzinska
authors.forename: Michael
authors.initials: M
authors.lastname: Weller
authors.forename: Burkhard
authors.initials: B
authors.lastname: Becher
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000276:immunology* / Q000628:therapy*; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005910:Glioma / Q000276:immunology* / Q000628:therapy*; D057809:HEK293 Cells; D006801:Humans; D007156:Immunologic Memory; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D018664:Interleukin-12 / Q000008:administration & dosage*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D013601:T-Lymphocytes / Q000166:cytology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology
chemical_list: D060908:CTLA-4 Antigen; D007166:Immunosuppressive Agents; D018664:Interleukin-12