title: Poxvirus-Based Active Immunotherapy with PD-1 and LAG-3 Dual Immune Checkpoint Inhibition Overcomes Compensatory Immune Regulation, Yielding Complete Tumor Regression in Mice.
abstract: Poxvirus-based active immunotherapies mediate anti-tumor efficacy by triggering broad and durable Th1 dominated T cell responses against the tumor. While monotherapy significantly delays tumor growth, it often does not lead to complete tumor regression. It was hypothesized that the induced robust infiltration of IFNγ-producing T cells into the tumor could provoke an adaptive immune evasive response by the tumor through the upregulation of PD-L1 expression. In therapeutic CT26-HER-2 tumor models, MVA-BN-HER2 poxvirus immunotherapy resulted in significant tumor growth delay accompanied by a robust, tumor-infiltrating T cell response that was characterized by low to mid-levels of PD-1 expression on T cells. As hypothesized, this response was countered by significantly increased PD-L1 expression on the tumor and, unexpectedly, also on infiltrating T cells. Synergistic benefit of anti-tumor therapy was observed when MVA-BN-HER2 immunotherapy was combined with PD-1 immune checkpoint blockade. Interestingly, PD-1 blockade stimulated a second immune checkpoint molecule, LAG-3, to be expressed on T cells. Combining MVA-BN-HER2 immunotherapy with dual PD-1 plus LAG-3 blockade resulted in comprehensive tumor regression in all mice treated with the triple combination therapy. Subsequent rejection of tumors lacking the HER-2 antigen by treatment-responsive mice without further therapy six months after the original challenge demonstrated long lasting memory and suggested that effective T cell immunity to novel, non-targeted tumor antigens (antigen spread) had occurred. These data support the clinical investigation of this triple therapy regimen, especially in cancer patients harboring PD-L1neg/low tumors unlikely to benefit from immune checkpoint blockade alone.
authors.affiliation: Bavarian Nordic, Inc., Redwood City, California, United States of America.
authors.forename: Susan P
authors.initials: SP
authors.lastname: Foy
authors.affiliation: Bavarian Nordic, Inc., Redwood City, California, United States of America.
authors.forename: Barbara
authors.initials: B
authors.lastname: Sennino
authors.affiliation: Bavarian Nordic, Inc., Redwood City, California, United States of America.
authors.forename: Tracy
authors.initials: T
authors.lastname: dela Cruz
authors.affiliation: Bavarian Nordic, Inc., Redwood City, California, United States of America.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Cote
authors.affiliation: Bavarian Nordic, Inc., Redwood City, California, United States of America.
authors.forename: Evan J
authors.initials: EJ
authors.lastname: Gordon
authors.affiliation: Bavarian Nordic, Inc., Redwood City, California, United States of America.
authors.forename: Felicia
authors.initials: F
authors.lastname: Kemp
authors.affiliation: Bavarian Nordic, Inc., Redwood City, California, United States of America.
authors.forename: Veronica
authors.initials: V
authors.lastname: Xavier
authors.affiliation: Bavarian Nordic, Inc., Redwood City, California, United States of America.
authors.forename: Alex
authors.initials: A
authors.lastname: Franzusoff
authors.affiliation: Bavarian Nordic, Inc., Redwood City, California, United States of America.
authors.forename: Ryan B
authors.initials: RB
authors.lastname: Rountree
authors.affiliation: Bavarian Nordic, Inc., Redwood City, California, United States of America.
authors.forename: Stefanie J
authors.initials: SJ
authors.lastname: Mandl
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D007111:Immunity, Cellular; D007167:Immunotherapy; D051379:Mice; D009374:Neoplasms, Experimental / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D011212:Poxviridae / Q000235:genetics / Q000276:immunology*; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D015703:Antigens, CD; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D000093322:Lymphocyte Activation Gene 3 Protein