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dc.contributor.author
Mineharu, Yohei
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Muhammad, AKM Ghulam
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Yagiz, Kader
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Candolfi, Marianela
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Kroeger, Kurt M.
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Xiong, Weidong
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Puntel, Mariana
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Liu, Chunyan
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Levy, Eva
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Lugo, Claudia
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Kocharian, Adrina
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Allison, James P.
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Curran, Michael A.
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Lowenstein, Pedro R.
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Castro, Maria G.
dc.date.available
2019-01-08T19:06:36Z
dc.date.issued
2012-10
dc.identifier.citation
Mineharu, Yohei; Muhammad, AKM Ghulam; Yagiz, Kader; Candolfi, Marianela; Kroeger, Kurt M.; et al.; Gene Therapy-Mediated Reprogramming Tumor Infiltrating T Cells Using IL-2 and Inhibiting NF-κB Signaling Improves the Efficacy of Immunotherapy in a Brain Cancer Model; Springer; Neurotherapeutics; 9; 4; 10-2012; 827-843
dc.identifier.issn
1933-7213
dc.identifier.uri
http://hdl.handle.net/11336/67675
dc.description.abstract
Immune-mediated gene therapy using adenovirus expressing Flt3 ligand and thymidine kinase followed by ganciclovir administration (Flt3/TK) effectively elicits tumor regression in preclinical glioma models. Herein, we assessed new strategies to optimize Flt3L/TK therapeutic efficacy in a refractory RG2 orthotopic glioblastoma model. Specifically, we aimed to optimize the therapeutic efficacy of Flt3L/TK treatment in the RG2 model by overexpressing the following genes within the brain tumor microenvironment: 1) a TK mutant with enhanced cytotoxicity (SR39 mutant TK), 2) Flt3L-IgG fusion protein that has a longer half-life, 3) CD40L to stimulate DC maturation, 4) T helper cell type 1 polarizing dendritic cell cytokines interleukin-12 or C-X-C motif ligand 10 chemokine (CXCL)-10, 5) C-C motif ligand 2 chemokine (CCL2) or C-C motif ligand 3 chemokine (CCL3) to enhance dendritic cell recruitment into the tumor microenvironment, 6) T helper cell type 1 cytokines interferon-γ or interleukin-2 to enhance effector T-cell functions, and 7) IκBα or p65RHD (nuclear factor kappa-B [NF-κB] inhibitors) to suppress the function of Foxp3+ Tregs and enhanced effector T-cell functions. Anti-tumor immunity and tumor specific effector T-cell functions were assessed by cytotoxic T lymphocyte assay and intracellular IFN-γ staining. Our data showed that overexpression of interferon-γ or interleukin-2, or inhibition of the nuclear factor kappa-B within the tumor microenvironment, enhanced cytotoxic T lymphocyte-mediated immune responses and successfully extended the median survival of rats bearing intracranial RG2 when combined with Flt3L/TK. These findings indicate that enhancement of T-cell functions constitutes a critical therapeutic target to overcome immune evasion and enhance therapeutic efficacy for brain cancer. In addition, our study provides novel targets to be used in combination with immune-therapeutic strategies for glioblastoma, which are currently being tested in the clinic.
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application/pdf
dc.language.iso
eng
dc.publisher
Springer
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dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.subject
ADENOVIRAL VECTORS
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GENE THERAPY
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GLIOBLASTOMA
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HSV1-TK
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IMMUNOTHERAPY
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Otras Biotecnologías de la Salud
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Biotecnología de la Salud
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CIENCIAS MÉDICAS Y DE LA SALUD
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dc.title
Gene Therapy-Mediated Reprogramming Tumor Infiltrating T Cells Using IL-2 and Inhibiting NF-κB Signaling Improves the Efficacy of Immunotherapy in a Brain Cancer Model
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2019-01-02T19:38:42Z
dc.identifier.eissn
1878-7479
dc.journal.volume
9
dc.journal.number
4
dc.journal.pagination
827-843
dc.journal.pais
Alemania
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dc.description.fil
Fil: Mineharu, Yohei. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos. University of California at Los Angeles; Estados Unidos
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Fil: Muhammad, AKM Ghulam. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos. University of California at Los Angeles; Estados Unidos
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Fil: Yagiz, Kader. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos. University of California at Los Angeles; Estados Unidos
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Fil: Candolfi, Marianela. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos. University of California at Los Angeles; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
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Fil: Kroeger, Kurt M.. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos. University of California at Los Angeles; Estados Unidos
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Fil: Xiong, Weidong. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos. University of California at Los Angeles; Estados Unidos
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Fil: Puntel, Mariana. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos. University of California at Los Angeles; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
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Fil: Liu, Chunyan. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos. University of California at Los Angeles; Estados Unidos
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Fil: Levy, Eva. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos. University of California at Los Angeles; Estados Unidos
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Fil: Lugo, Claudia. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos. University of California at Los Angeles; Estados Unidos
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Fil: Kocharian, Adrina. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos. University of California at Los Angeles; Estados Unidos
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Fil: Allison, James P.. Howard Hughes Medical Institute; Estados Unidos
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Fil: Curran, Michael A.. Howard Hughes Medical Institute; Estados Unidos
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Fil: Lowenstein, Pedro R.. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos. University of California at Los Angeles; Estados Unidos. University of Michigan; Estados Unidos
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Fil: Castro, Maria G.. Cedars Sinai Medical Center. Gene Therapeutics Research Institute; Estados Unidos. University of California at Los Angeles; Estados Unidos. University of Michigan; Estados Unidos
dc.journal.title
Neurotherapeutics
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dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/https://dx.doi.org/10.1007/s13311-012-0144-7
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/https://link.springer.com/article/10.1007%2Fs13311-012-0144-7
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