Journal Article

DKFZ-2021-00004

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Delta-24-RGD, an oncolytic adenovirus, increases survival and promotes proinflammatory immune landscape remodeling in models of AT/RT and CNS-PNET.

Garcia-Moure, M. ; Gonzalez-Huarriz, M. ; Labiano, S. ; Guruceaga, E. ; Bandres, E. ; Zalacain, M. ; Marrodan, L. ; de Andrea, C. E. ; Villalba Esparza, M. ; Martínez-Vélez, N. ; Laspidea, V. ; Puigdelloses, M. ; Gallego Perez-Larraya, J. ; Iñigo-Marco, I. ; Stripecke, R. ; Chan, J. A. ; Raabe, E. H. ; Kool, M.DKFZ* ; Gomez-Manzano, C. ; Fueyo, J. ; Patiño-García, A. ; Alonso, M. M.

2021
AACR Philadelphia, Pa. [u.a.]

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Please use a persistent id in citations: doi:10.1158/1078-0432.CCR-20-3313

Abstract: Atypical 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.

Note: 2021 Mar 15;27(6):1807-1820

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Contributing Institute(s):

1. B062 Pädiatrische Neuroonkologie (B062)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2021

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Essential Science Indicators ; IF >= 5 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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