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000166637 0247_ $$2doi$$a10.1158/1078-0432.CCR-20-3313
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000166637 0247_ $$2ISSN$$a1557-3265
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000166637 1001_ $$00000-0002-4365-7753$$aGarcia-Moure, Marc$$b0
000166637 245__ $$aDelta-24-RGD, an oncolytic adenovirus, increases survival and promotes proinflammatory immune landscape remodeling in models of AT/RT and CNS-PNET.
000166637 260__ $$aPhiladelphia, Pa. [u.a.]$$bAACR$$c2021
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000166637 500__ $$a2021 Mar 15;27(6):1807-1820
000166637 520__ $$aAtypical teratoid/rhabdoid tumors (AT/RTs) and primitive neuroectodermal tumors (CNS-PNETs) are pediatric brain tumors with poor survival and life-long negative side effects. Here, the aim was to characterize the efficacy and safety of the oncolytic adenovirus Delta-24-RGDs, which selectively replicates in and kills tumor cells.Delta-24-RGD determinants for infection and replication were evaluated in patient expression data sets. Viral replication and cytotoxicity were assessed invitro in a battery of CNS-PNET and AT/RT cell lines. In vivo, efficacy was determined in different orthotopic mouse models, including early and established tumor models, a disseminated AT/RT lesion model and immunocompetent humanized mouse models (hCD34+-NSG-SGM3).Delta-24-RGD infected and replicated efficiently in all the cell lines tested. In addition, the virus induced dose-dependent cytotoxicity (IC50 below 1 PFU/cell) and the release of immunogenic markers. Invivo, a single intratumoral Delta-24-RGD injection (107 or 108 PFU) significantly increased survival and led to long-term survival in AT/RT and PNET models. Delta-24-RGD hindered the dissemination of AT/RTs and increased survival, leading to 70% of long-term survivors. Of relevance, viral administration to established tumor masses (30 days after engraftment) showed therapeutic benefit. In humanized immunocompetent models, Delta-24-RGD significantly extended the survival of mice bearing AT/RTs or PNETs (ranging from 11 to 27 days) and did not display any toxicity associated with inflammation. Immunophenotyping of Delta-24-RGD-treated tumors revealed increased CD8+ T cell infiltration.Delta-24-RGD is a feasible therapeutic option for AT/RTs and CNS-PNETs. This work constitutes the basis for potential translation to the clinical setting.
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000166637 7001_ $$aGonzalez-Huarriz, Marisol$$b1
000166637 7001_ $$aLabiano, Sara$$b2
000166637 7001_ $$00000-0003-0547-681X$$aGuruceaga, Elizabeth$$b3
000166637 7001_ $$aBandres, Eva$$b4
000166637 7001_ $$aZalacain, Marta$$b5
000166637 7001_ $$aMarrodan, Lucia$$b6
000166637 7001_ $$ade Andrea, Carlos E$$b7
000166637 7001_ $$aVillalba Esparza, María$$b8
000166637 7001_ $$aMartínez-Vélez, Naiara$$b9
000166637 7001_ $$aLaspidea, Virginia$$b10
000166637 7001_ $$aPuigdelloses, Montserrat$$b11
000166637 7001_ $$00000-0003-2969-0116$$aGallego Perez-Larraya, Jaime$$b12
000166637 7001_ $$aIñigo-Marco, Ignacio$$b13
000166637 7001_ $$aStripecke, Renata$$b14
000166637 7001_ $$00000-0001-9798-1551$$aChan, Jennifer A$$b15
000166637 7001_ $$aRaabe, Eric H$$b16
000166637 7001_ $$0P:(DE-He78)4c28e2aade5f44d8eca9dd8e97638ec8$$aKool, Marcel$$b17$$udkfz
000166637 7001_ $$00000-0002-1259-2133$$aGomez-Manzano, Candelaria$$b18
000166637 7001_ $$00000-0001-6941-2335$$aFueyo, Juan$$b19
000166637 7001_ $$00000-0002-4066-8203$$aPatiño-García, Ana$$b20
000166637 7001_ $$00000-0002-7520-7351$$aAlonso, Marta M$$b21
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