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Rountree R.B.,BN ImmunoTherapeutics | Mandl S.J.,BN ImmunoTherapeutics | Nachtwey J.M.,BN ImmunoTherapeutics | Dalpozzo K.,BN ImmunoTherapeutics | And 7 more authors.
Cancer Research | Year: 2011

MVA-BN-PRO (BN ImmunoTherapeutics) is a candidate immunotherapy product for the treatment of prostate cancer. It encodes 2 tumor-associated antigens, prostate-specific antigen (PSA), and prostatic acid phosphatase (PAP), and is derived from the highly attenuated modified vaccinia Ankara (MVA) virus stock known as MVA-BN. Past work has shown that the immunogenicity of antigens can be improved by targeting their localization to exosomes, which are small, 50- to 100-nm diameter vesicles secreted by most cell types. Exosome targeting is achieved by fusing the antigen to the C1C2 domain of the lactadherin protein. To test whether exosome targeting would improve the immunogenicity of PSA and PAP, 2 additional versions of MVA-BN-PRO were produced, targeting either PSA (MVA-BN-PSA-C1C2) or PAP (MVA-BN-PAP-C1C2) to exosomes, while leaving the second transgene untargeted. Treatment of mice with MVA-BN-PAP-C1C2 led to a striking increase in the immune response against PAP. Anti-PAP antibody titers developed more rapidly and reached levels that were 10- to 100-fold higher than those for mice treated with MVA-BN-PRO. Furthermore, treatment with MVA-BN-PAP-C1C2 increased the frequency of PAP-specific T cells 5-fold compared with mice treated with MVA-BN-PRO. These improvements translated into a greater frequency of tumor rejection in a PAP-expressing solid tumor model. Likewise, treatment with MVA-BN-PSA-C1C2 increased the antigenicity of PSA compared with treatment with MVA-BN-PRO and resulted in a trend of improved antitumor efficacy in a PSA-expressing tumor model. These experiments confirm that targeting antigen localization to exosomes is a viable approach for improving the therapeutic potential of MVA-BN-PRO in humans. ©2011 AACR.

Mandl S.J.,BN ImmunoTherapeutics | Rountree R.B.,BN ImmunoTherapeutics | Dalpozzo K.,BN ImmunoTherapeutics | Do L.,BN ImmunoTherapeutics | And 7 more authors.
Cancer Immunology, Immunotherapy | Year: 2012

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. © 2011 The Author(s).

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