title: Immunotherapy with MVA-BN®-HER2 induces HER-2-specific Th1 immunity and alters the intratumoral balance of effector and regulatory T cells.
abstract: MVA-BN®-HER2 is a new candidate immunotherapy designed for the treatment of HER-2-positive breast cancer. Here, we demonstrate that a single treatment with MVA-BN®-HER2 exerts potent anti-tumor efficacy in a murine model of experimental pulmonary metastasis. This anti-tumor efficacy occurred despite a strong tumor-mediated immunosuppressive environment characterized by a high frequency of regulatory T cells (T(reg)) in the lungs of tumor-bearing mice. Immunogenicity studies showed that treatment with MVA-BN®-HER2 induced strongly Th1-dominated HER-2-specific antibody and T-cell responses. MVA-BN®-HER2-induced anti-tumor activity was characterized by an increased infiltration of lungs with highly activated, HER-2-specific, CD8+CD11c+ T cells accompanied by a decrease in the frequency of T(reg) cells in the lung, resulting in a significantly increased ratio of effector T cells to T(reg) cells. In contrast, administration of HER2 protein formulated in Complete Freund's Adjuvant (CFA) induced a strongly Th2-biased immune response to HER-2. However, this did not lead to significant infiltration of the tumor-bearing lungs by CD8+ T cells or the decrease in the frequency of T(reg) cells nor did it result in anti-tumor efficacy. In vivo depletion of CD8+ cells confirmed that CD8 T cells were required for the anti-tumor activity of MVA-BN®-HER2. Furthermore, depletion of CD4+ or CD25+ cells demonstrated that tumor-induced T(reg) cells promoted tumor growth and that CD4 effector cells also contribute to MVA-BN®-HER2-mediated anti-tumor efficacy. Taken together, our data demonstrate that treatment with MVA-BN®-HER2 controls tumor growth through mechanisms including the induction of Th1-biased HER-2-specific immune responses and the control of tumor-mediated immunosuppression.
authors.affiliation: Department of Research, BN ImmunoTherapeutics, 2425 Garcia Ave, Mountain View, CA 94043, USA. stefanie.mandl@bn-it.com
authors.forename: Stefanie J
authors.initials: SJ
authors.lastname: Mandl
authors.forename: Ryan B
authors.initials: RB
authors.lastname: Rountree
authors.forename: Katie
authors.initials: K
authors.lastname: Dalpozzo
authors.forename: Lisa
authors.initials: L
authors.lastname: Do
authors.forename: John R
authors.initials: JR
authors.lastname: Lombardo
authors.forename: Peter L
authors.initials: PL
authors.lastname: Schoonmaker
authors.forename: Ulrike
authors.initials: U
authors.lastname: Dirmeier
authors.forename: Robin
authors.initials: R
authors.lastname: Steigerwald
authors.forename: Thierry
authors.initials: T
authors.lastname: Giffon
authors.forename: Reiner
authors.initials: R
authors.lastname: Laus
authors.forename: Alain
authors.initials: A
authors.lastname: Delcayre
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D000818:Animals; D016175:B-Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D019496:Cancer Vaccines / Q000276:immunology / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000201:enzymology / Q000473:pathology / Q000628:therapy*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D007167:Immunotherapy / Q000379:methods*; D008175:Lung Neoplasms / Q000276:immunology / Q000556:secondary / Q000628:therapy; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000201:enzymology / Q000276:immunology* / Q000473:pathology
chemical_list: D019496:Cancer Vaccines; D018719:Erb-b2 Receptor Tyrosine Kinases