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

被引:18
作者
Mandl, Stefanie J. [1 ]
Rountree, Ryan B. [1 ]
Dalpozzo, Katie [1 ]
Do, Lisa [1 ]
Lombardo, John R. [1 ]
Schoonmaker, Peter L. [1 ]
Dirmeier, Ulrike [2 ]
Steigerwald, Robin [2 ]
Giffon, Thierry [1 ]
Laus, Reiner [1 ]
Delcayre, Alain [1 ]
机构
[1] BN ImmunoTherapeut, Dept Res, Mountain View, CA 94043 USA
[2] Bavarian Nord GmbH, D-82152 Martinsried, Germany
关键词
Immunotherapy; Modified Vaccinia Ankara (MVA); Th1; Immunosuppression; Breast cancer; Regulatory T cells; HER-2; ATTENUATED SMALLPOX VACCINE; LUNG-CANCER; VIRUS-INFECTION; TUMOR-IMMUNITY; OVARIAN-CANCER; CUTTING EDGE; IN-VIVO; MECHANISMS; RESPONSES; ANTI-4-1BB;
D O I
10.1007/s00262-011-1077-4
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
收藏
页码:19 / 29
页数:11
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