<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "Unraveling Determinants of Efficacy in Measles Immunovirotherapy"^^ . "Replicating oncolytic viruses (OVs) that are able to selectively destroy malignant cells are\r\nemerging as clinically relevant cancer therapeutics. Along with direct tumor cell lysis, activation of specific anti-tumor immune responses contributes to efficacy of virotherapy, allowing to consider it for a type of cancer immunotherapy. Combinations with different\r\nimmunomodulation strategies have been shown to enhance the immunostimulatory effects\r\nof OVs and contribute to increased therapeutic efficacy. Based on the hypothesis that certain immunomodulation types might more efficiently contribute to efficacy of virotherapy\r\nin a given tumor type, this study compared efficacy of oncolytic measles vectors encoding immunomodulators from different classes. Furthermore, to identify immune effector\r\nmechanisms associated with successful therapeutic strategies, analysis of the tumor immune\r\nenvironment was performed following treatment with the most promising vectors.\r\nMeasles Schwarz vaccine strain vectors (MeVac) encoding immunomodulators to target the main phases in establishment of an anti-tumor immune response were developed.\r\nTherapeutic efficacy of the novel vectors was compared in a fully immunocompetent murine\r\ncolon adenocarcinoma model, MC38cea. MeVac vectors encoding an antibody against the\r\nnegative T cell regulator PD-L1 (anti-PD-L1) and a fusion protein of murine interleukin-12\r\n(FmIL-12), respectively, were identified as the most promising in terms of increased survival\r\nof animals. Importantly, MeVac encoding FmIL-12 was the most effective, ensuring complete\r\ntumor remissions in 90% of the treated animals. After MeVac therapy, long-term survivors\r\nrejected secondary tumor engraftments, indicating establishment of a systemic anti-tumor\r\nimmune response. Profiling of the tumor environment four days after the last treatment with\r\nthe anti-PD-L1 encoding vector revealed a slight benefit for cell mediated immune responses,\r\nas observed by a slight upregulation of the effector cytokines IFN-γ and TNF-α as well as an\r\nincrease in the intratumoral T cell population. More pronounced modulation of the tumor\r\nimmune environment was observed following treatment with the FmIL-12 encoding vector.\r\nOne day after treatment with MeVac encoding FmIL-12 an increase of effector cytokines\r\nIFN-γ and TNF-α was observed, suggesting activation of a cell mediated immune response.\r\nAnalysis of tumor infiltrating lymphocytes revealed an increase in the T cell population, a\r\nmassive decrease in the natural killer (NK) cell population and upregulation of an activation\r\nmarker on NK cells. These results indicated early activation of the immune effector cells\r\nfollowing treatment with MeVac encoding FmIL-12, which in case of the NK cells could be\r\nassociated with activation induced cell death. Furthermore, immune cell depletion experiments revealed that the CD4+ T cells and NK cells do not importantly contribute to the\r\ntherapeutic efficacy of the MeVac encoding FmIL-12 in this model, but that the cytotoxic\r\nCD8+ T cells are essential.\r\nThis study presents MeVac encoding FmIL-12 as an effective therapeutic for activation\r\nof cell mediated anti-tumor immune responses. Furthermore, the MeVac vector is established as a flexible platform for targeted local delivery of immunomodulators. The tumor\r\nimmune profiling data provide a basis for further rational vector modifications to develop\r\nimmunomodulation strategies tailored to the individual tumor immune environment."^^ . "2017" . . . . . . . "Rūta"^^ . "Veinalde"^^ . "Rūta Veinalde"^^ . . . . . . "Unraveling Determinants of Efficacy in Measles Immunovirotherapy (PDF)"^^ . . . "R.Veinalde_Thesis_print.pdf"^^ . . . "Unraveling Determinants of Efficacy in Measles Immunovirotherapy (Other)"^^ . . . . . . "indexcodes.txt"^^ . . . "Unraveling Determinants of Efficacy in Measles Immunovirotherapy (Other)"^^ . . . . . . "lightbox.jpg"^^ . . . "Unraveling Determinants of Efficacy in Measles Immunovirotherapy (Other)"^^ . . . . . . "preview.jpg"^^ . . . "Unraveling Determinants of Efficacy in Measles Immunovirotherapy (Other)"^^ . . . . . . "medium.jpg"^^ . . . "Unraveling Determinants of Efficacy in Measles Immunovirotherapy (Other)"^^ . . . . . . "small.jpg"^^ . . "HTML Summary of #23094 \n\nUnraveling Determinants of Efficacy in Measles Immunovirotherapy\n\n" . "text/html" . . . "500 Naturwissenschaften und Mathematik"@de . "500 Natural sciences and mathematics"@en . .