Publicaciones científicas

Delta-24-RGD, an Oncolytic Adenovirus, Increases Survival and Promotes Proinflammatory Immune Landscape Remodeling in Models of AT/RT and CNS-PNET

29-dic-2020 | Revista: Clinical Cancer Research

Marc Garcia-Moure #  1   2   3 , Marisol Gonzalez-Huarriz #  4   2   3 , Sara Labiano  4   2   3 , Elizabeth Guruceaga  4   5 , Eva Bandres  4   6 , Marta Zalacain  4   2   3 , Lucia Marrodan  4   2   3 , Carlos de Andrea  4   7 , Maria Villalba  4   7   8 , Naiara Martinez-Velez  4   2   3 , Virginia Laspidea  4   2   3 , Montse Puigdelloses  4   2   9 , Jaime Gallego Perez-Larraya  4   2   9 , Ignacio Iñigo-Marco  4   2   3 , Renata Stripecke  10 , Jennifer A Chan  11 , Eric H Raabe  12   13 , Marcel Kool  14   15   16 , Candelaria Gomez-Manzano  17   18 , Juan Fueyo  18   19 , Ana Patiño-García  4   2   3 , Marta M Alonso  1   2   3


Purpose: Atypical teratoid/rhabdoid tumors (AT/RT) and central nervous system primitive neuroectodermal tumors (CNS-PNET) 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-RGD, which selectively replicates in and kills tumor cells.

Experimental design: Delta-24-RGD determinants for infection and replication were evaluated in patient expression datasets. Viral replication and cytotoxicity were assessed in vitro 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).

Results: Delta-24-RGD infected and replicated efficiently in all the cell lines tested. In addition, the virus induced dose-dependent cytotoxicity [IC50 value below 1 plaque-forming unit (PFU)/cell] and the release of immunogenic markers. In vivo, 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.

Conclusions: 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.

CITA DEL ARTÍCULO  Clin Cancer Res. 2020 Dec 29. doi: 10.1158/1078-0432.CCR-20-3313