Immunotherapy with MVA-BN®-HER2 induces HER-2-specific Th1 immunity and alters the intratumoral balance of effector and regulatory T cells

MVA-BN (R)-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 (R)-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 (R)-HER2 induced strongly Th1-dominated HER-2-specific antibody and T-cell responses. MVA-BN (R)-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 (Treg) 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 (R)-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 (R)-HER2-mediated anti-tumor efficacy. Taken together, our data demonstrate that treatment with MVA-BN (R) -HER2 controls tumor growth through mechanisms including the induction of Th1-biased HER-2-specific immune responses and the control of tumor-mediated immunosuppression.