title: Poxvirus-based active immunotherapy synergizes with CTLA-4 blockade to increase survival in a murine tumor model by improving the magnitude and quality of cytotoxic T cells.
abstract: The dramatic clinical benefit of immune checkpoint blockade for a fraction of cancer patients suggests the potential for further clinical benefit in a broader cancer patient population by combining immune checkpoint inhibitors with active immunotherapies. The anti-tumor efficacy of MVA-BN-HER2 poxvirus-based active immunotherapy alone or in combination with CTLA-4 checkpoint blockade was investigated in a therapeutic CT26-HER-2 lung metastasis mouse model. MVA-BN-HER2 immunotherapy significantly improved the median overall survival compared to untreated controls or CTLA-4 blockade alone (p < 0.001). Robust synergistic efficacy was achieved with the combination therapy (p < 0.01). Improved survival following MVA-BN-HER2 administration was accompanied by increased tumor infiltration by HER-2-specific cytotoxic T lymphocytes (CTL). These tumor-specific CTL had characteristics similar to antiviral CTL, including strong expression of activation markers and co-expression of IFNγ and TNFα. Combination with CTLA-4 blockade significantly increased the magnitude of HER-2-specific T cell responses, with a higher proportion co-expressing TNFα and/or IL-2 with IFNγ. Furthermore, in mice treated with MVA-BN-HER2 (alone or in combination with CTLA-4 blockade), the inducible T cell co-stimulator (ICOS) protein was expressed predominantly on CD4 and CD8 effector T cells but not on regulatory T cells (T(reg)). In contrast, mice left untreated or treated solely with CTLA-4 blockade harbored elevated ICOS(+) Treg, a phenotype associated with highly suppressive activity. In conclusion, poxvirus-based active immunotherapy induced robust tumor infiltration by highly efficient effector T cells. Combination with CTLA-4 immune checkpoint blockade amplified this response resulting in synergistically improved efficacy. These hypothesis-generating data may help elucidate evidence of enhanced clinical benefit from combining CTLA-4 blockade with poxvirus-based active immunotherapy.
authors.affiliation: Bavarian Nordic, Inc., 595 Penobscot Dr., Redwood City, CA, 94063, USA. SusanPFoy@gmail.com.
authors.forename: Susan P
authors.initials: SP
authors.lastname: Foy
authors.affiliation: Bavarian Nordic, Inc., 595 Penobscot Dr., Redwood City, CA, 94063, USA.
authors.forename: Stefanie J
authors.initials: SJ
authors.lastname: Mandl
authors.affiliation: Bavarian Nordic, Inc., 595 Penobscot Dr., Redwood City, CA, 94063, USA.
authors.forename: Tracy
authors.initials: T
authors.lastname: dela Cruz
authors.affiliation: Bavarian Nordic, Inc., 595 Penobscot Dr., Redwood City, CA, 94063, USA.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Cote
authors.affiliation: Bavarian Nordic, Inc., 595 Penobscot Dr., Redwood City, CA, 94063, USA.
authors.forename: Evan J
authors.initials: EJ
authors.lastname: Gordon
authors.affiliation: Bavarian Nordic, Inc., 595 Penobscot Dr., Redwood City, CA, 94063, USA.
authors.forename: Erica
authors.initials: E
authors.lastname: Trent
authors.affiliation: Bavarian Nordic, Inc., 595 Penobscot Dr., Redwood City, CA, 94063, USA.|ExoThera LLC, 675 Olive Street, Menlo Park, CA, 94025, USA.
authors.forename: Alain
authors.initials: A
authors.lastname: Delcayre
authors.affiliation: Bavarian Nordic, Inc., 595 Penobscot Dr., Redwood City, CA, 94063, USA.
authors.forename: James
authors.initials: J
authors.lastname: Breitmeyer
authors.affiliation: Bavarian Nordic, Inc., 595 Penobscot Dr., Redwood City, CA, 94063, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Franzusoff
authors.affiliation: Bavarian Nordic, Inc., 595 Penobscot Dr., Redwood City, CA, 94063, USA.
authors.forename: Ryan B
authors.initials: RB
authors.lastname: Rountree
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology* / Q000494:pharmacology; D045744:Cell Line, Tumor; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004357:Drug Synergism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D008175:Lung Neoplasms / Q000276:immunology / Q000517:prevention & control / Q000556:secondary; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D016019:Survival Analysis; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology; D059016:Tumor Microenvironment / Q000187:drug effects / Q000276:immunology; D014616:Vaccinia virus / Q000235:genetics / Q000276:immunology*
chemical_list: D000906:Antibodies; D060908:CTLA-4 Antigen; D019496:Cancer Vaccines; D016207:Cytokines
keywords: Active immunotherapy; Anti-CTLA-4; Cancer; Immune checkpoint blockade; Modified Vaccinia Ankara (MVA); Poxvirus