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, Marisol Gonzalez-Huarriz, Sara Labiano, Elizabeth Guruceaga, Eva Bandres, Marta Zalacain, Lucia Marrodan, Carlos de Andrea, Maria Villalba, Naiara Martinez-Velez, Virginia Laspidea, Montse Puigdelloses, Jaime Gallego Perez-Larraya, Ignacio Iñigo-Marco, Renata Stripecke, Jennifer A. Chan, Eric H. Raabe, Marcel Kool, Candelaria Gomez-Manzano, Juan FueyoAna Patiño-García, Marta M. Alonso

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

6 Citaten (Scopus)

Samenvatting

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 (hCD34þNSG-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 CD8þ 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.

Originele taal-2Engels
Pagina's (van-tot)1807-1820
Aantal pagina's14
TijdschriftClinical Cancer Research
Volume27
Nummer van het tijdschrift6
DOI's
StatusGepubliceerd - mrt. 2021

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