MVA-BN® HER2
Breast cancer immunotherapy product candidate
MVA-BN® HER2 is designed to express sequences that control
immunity to HER2-Neu antigen (HER2). HER2 is a growth factor
receptor that is over-expressed by approximately 20 - 30% of
patients with localized breast cancer, and is important for the
growth of the tumor. HER2 has been validated as a tumor antigen
target through numerous preclinical and clinical studies. This is
notably exemplified by the efficacy of Herceptin, a humanized
anti-HER2 monoclonal antibody, FDA and EMEA approved for treatment
in both metastatic and adjuvant disease settings. Active
immunotherapy against HER2 is being studied by numerous
investigators at an early stage of development using a variety of
forms of HER2 including wild-type, truncated, peptide fragments,
and modified forms. Bavarian Nordic's approach is to utilize the
MVA-BN® vector, engineered to encode a modified form of HER2,
to generate endogenous immune response to the critical tumor
antigen.
Publications
Immunotherapy with MVA-BN®-HER2 induces
HER-2-specific Th1 immunity and alters the intratumoral balance of
effector and regulatory T cells
Mandl SJ, Rountree RB, Dalpozzo K, Do L, Lombardo JR,
Schoonmaker PL, Dirmeier U, Steigerwald R, Giffon T, Laus R,
Delcayre A.
Cancer Immunol Immunother. 2011 Aug 7. [Epub ahead of
print]
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.
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