Abstract 2420: Modified vaccinia Ankara (MVA) expressing survivin combined with gemcitabine generates specific antitumor effects in a murine pancreatic carcinoma model

Division of General and Oncologic Surgery, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010-3000, USA.
Cancer Immunology and Immunotherapy (Impact Factor: 3.94). 10/2010; 60(1):99-109. DOI: 10.1007/s00262-010-0923-0
Source: PubMed


Survivin is overexpressed by 70-80% of pancreatic cancers, and is associated with resistance to chemotherapy and a poor prognosis. Gemcitabine has been a standard treatment for patients with advanced pancreatic cancer for a decade. Recent reports have demonstrated that gemcitabine treatment attenuates the tumor-suppressive environment by eliminating CD11b(+)/Gr-1(+) myeloid-derived suppressor cells (MDSCs). We hypothesize that a cancer vaccine targeting survivin can achieve enhanced efficacy when combined with gemcitabine. In this study, we tested this hypothesis using modified vaccinia Ankara (MVA) expressing full-length murine survivin. The poorly immunogenic mouse pancreas adenocarcinoma cell line, Pan02, which expresses murine survivin and is syngeneic to C57BL/6, was used for this study. Immunization with MVA-survivin resulted in a modest therapeutic antitumor effect on established Pan02 tumors. When administered with gemcitabine, MVA-survivin immunization resulted in significant tumor regression and prolonged survival. The enhanced vaccine efficacy was associated with decreased CD11b(+)/Gr-1(+) MDSCs. To analyze the survivin-specific immune response to MVA-survivin immunization, we utilized a peptide library of 15mers with 11 residues overlapping from full-length murine survivin. Splenocytes from mice immunized with MVA-survivin produced intracellular γ-interferon in response to in vitro stimulation with the overlapping peptide library. Increased survivin-specific CD8(+) T cells that specifically recognized the Pan02 tumor line were seen in mice treated with MVA-survivin and gemcitabine. These data suggest that vaccination with MVA-survivin in combination with gemcitabine represents an attractive strategy to overcome tumor-induced peripheral immune tolerance, and this effect has potential for clinical benefit in pancreatic cancer.

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Available from: Don J Diamond, Apr 05, 2015
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    • "Le at al. showed that weekly gemcitabine treatments reduced tumor size and levels of splenic MDSCs in mice bearing 4T1 tumors [76]. Gemcitabine treatment of mice bearing established Panc02 pancreatic adenocarcinomas prior to administration of a modified Vaccinia Ankara (MVA) based viral vaccine against the murine survivin protein led to the greatest reduction in tumor volume compared to controls [15]. Inhibition of MDSC accumulation with gemcitabine also enhanced the activity of a Her-2/neu adenoviral vector vaccine [21]. "
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    ABSTRACT: Myeloid Derived Suppressor Cells (MDSC) are a heterogeneous population of immature myeloid cells that are increased in states of cancer, inflammation and infection. In malignant states, MDSC are induced by tumor secreted growth factors. MDSC play an important part in suppression of host immune responses through several mechanisms such as production of arginase 1, release of reactive oxygen species and nitric oxide and secretion of immune-suppressive cytokines. This leads to a permissive immune environment necessary for the growth of malignant cells. MDSC may also contribute to angiogenesis and tumor invasion. This review focuses on currently available strategies to inhibit MDSC in the treatment of cancer.
    07/2013; 1(1, article 10):10. DOI:10.1186/2051-1426-1-10
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    • "Presently, many vaccines targeting survivin are being evaluated both in pre-clinical and clinical trials. A modified vaccinia Ankara expressing survivin combined with gemcitabine has been reported to generate specific anti-tumor effects in a murine pancreatic carcinoma model [4]. A survivin peptide vaccine was shown to elicit therapeutic effects with a T helper cell supported cytotoxic T lymphocyte (CTL) responses against murine cerebral glioma [5]. "
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    ABSTRACT: As an ideal tumor antigen, survivin has been widely used for tumor immunotherapy. Nevertheless, no effective protein vaccine targeting survivin has been reported, which may be due to its poor ability to induce cellular immunity. Thus, a suitable immunoadjuvant and optimized immunization strategy can greatly enhance the cellular immune response to this protein vaccine. DDA/MPL (monophosphoryl lipid A formulated with cationic dimethyldioctadecylammonium) has been reported to enhance the antigen uptake and presentation to T cells as an adjuvant. Meanwhile, a heterologous prime-boost strategy can enhance the cellular immunity of a protein vaccine by applying different antigen-presenting systems. Here, DDA/MPL and an adenovirus prime-protein boost strategy were applied to enhance the specific anti-tumor immunity of a truncated survivin protein vaccine. Antigen-specific IFN-γ-secreting T cells were increased by 10-fold, and cytotoxic T lympohocytes (CTLs) were induced effectively when the protein vaccine was combined with the DDA/MPL adjuvant. Meanwhile, the Th1 type cellular immune response was strongly enhanced and tumor inhibition was significantly increased by 96% with the adenovirus/protein prime-boost strategy, compared to the protein homologous prime-boost strategy. Moreover, this adjuvanted heterologous prime-boost strategy combined with oxaliplatin could significantly enhance the efficiency of tumor growth inhibition through promoting the proliferation of splenocytes. Thus, our results provide a novel vaccine strategy for cancer therapy using an adenovirus prime-protein boost strategy in a murine melanoma model, and its combination with oxaliplatin may further enhance the anti-tumor efficacy while alleviating side effects of the drug.
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