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