Mountain View, CA, United States
Mountain View, CA, United States

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PubMed | Bavarian Nordic, Urology Associates, Urology Clinics of North Texas, Advance Med Research and 5 more.
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2017

193 Background: MVA-BN-PRO is an investigational prostate cancer immunotherapy comprising of a highly attenuated non-replicating vaccinia virus engineered to encode prostate specific antigen (PSA) and prostate acid phosphatase (PAP) proteins. Preclinical studies in mouse tumor models demonstrated vaccine-mediated induction of anti-PSA and PAP specific immune responses and anti-tumor activity. Results of the open-label multi-center evaluation in subjects with non-metastatic castration resistant prostate cancer are presented.Eligible subjects had documented prostate cancer with a rising PSA while on androgen suppression therapy and were chemotherapy nave. Three cohorts of subjects were immunized subcutaneously receiving either 1, 2 or 4 injections of study drug (1 injection = 110Twenty-four subjects were dosed. All subjects completed the initial 3 vaccinations (treatment) and 21 subjects received 6 vaccinations (re-treatment). Seven responders received additional vaccinations during the extended treatment. No dose-limiting toxicities were reported. There were no reported Grade 3 treatment-related adverse events (AE). The most common related AEs were Grade 1 or 2 general disorders and administration site reactions.MVA-BN-PRO was well tolerated. Results from immune analysis and clinical activity measured by PSA levels or radiological progression will be presented.NCT00629057.


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).


PubMed | BN ImmunoTherapeutics
Type: Comparative Study | Journal: Journal of virological methods | Year: 2010

A flow cytometry-based immuno-titration titer assay was established to determine infectious unit (IU) and transducing unit (TU) of modified vaccinia Ankara (MVA) virus vectors. This titration method enumerates infected cells by measuring the expression of viral protein for IU and transgene protein for TU in individual cells after staining with fluorophore-conjugated antibodies. It presents many advantages over standard virus titration approaches, such as TCID(50) or plaque assay, for its convenience, rapidity and accuracy as illustrated by excellent assay linearity and reproducibility. Importantly, the IU and the TCID(50) assays generated similar batch-specific titer values when testing varied MVA-derived virus preparations. Assay development revealed that the post-infection time at which viral protein expression is evaluated, host cell type, and blocking the formation and release of progeny virion with nocodazole, an anti-microtubule agent or rifampin, a specific vaccinia virus assembly inhibitor, are critical parameters for the precision, robustness, and accuracy of IU titer determination. An added advantage of this assay is that it enables the concurrent determination of IU and transducing units (TU) by measuring the expression of a transgene product when testing recombinant viruses. The latter was demonstrated using a MVA vector carrying a human HER-2 gene fragment as model. Hence, this assay is very versatile in that it can be used to determine IU as well as multiple TU titers simultaneously. Furthermore, it can readily be adapted to other poxvirus vectors.


PubMed | BN ImmunoTherapeutics
Type: Journal Article | Journal: Cancer immunology, immunotherapy : CII | 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 Freunds 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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