Preclinical Testing of an Oncolytic Parvovirus in Ewing Sarcoma: Protoparvovirus H-1 Induces Apoptosis and Lytic Infection In Vitro but Fails to Improve Survival In Vivo
Jeannine Lacroix,
Zoltán Kis,
Rafael Josupeit,
Franziska Schlund,
Alexandra Stroh-Dege,
Monika Frank-Stöhr,
Barbara Leuchs,
Jörg R. Schlehofer,
Jean Rommelaere,
Christiane Dinsart
Affiliations
Jeannine Lacroix
Division of Tumor Virology, Program Infection, Inflammation and Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, Heidelberg 69120, Germany
Zoltán Kis
Division of Tumor Virology, Program Infection, Inflammation and Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, Heidelberg 69120, Germany
Rafael Josupeit
Division of Tumor Virology, Program Infection, Inflammation and Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, Heidelberg 69120, Germany
Franziska Schlund
Division of Tumor Virology, Program Infection, Inflammation and Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, Heidelberg 69120, Germany
Alexandra Stroh-Dege
Division of Tumor Virology, Program Infection, Inflammation and Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, Heidelberg 69120, Germany
Monika Frank-Stöhr
Division of Viral Transformation Mechanisms, Program Infection, Inflammation and Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, 69120 Heidelberg, Germany
Barbara Leuchs
Division of Tumor Virology, Program Infection, Inflammation and Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, Heidelberg 69120, Germany
Jörg R. Schlehofer
Division of Tumor Virology, Program Infection, Inflammation and Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, Heidelberg 69120, Germany
Jean Rommelaere
Division of Tumor Virology, Program Infection, Inflammation and Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, Heidelberg 69120, Germany
Christiane Dinsart
Division of Tumor Virology, Program Infection, Inflammation and Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, Heidelberg 69120, Germany
About 70% of all Ewing sarcoma (EWS) patients are diagnosed under the age of 20 years. Over the last decades little progress has been made towards finding effective treatment approaches for primarily metastasized or refractory Ewing sarcoma in young patients. Here, in the context of the search for novel therapeutic options, the potential of oncolytic protoparvovirus H-1 (H-1PV) to treat Ewing sarcoma was evaluated, its safety having been proven previously tested in adult cancer patients and its oncolytic efficacy demonstrated on osteosarcoma cell cultures. The effects of viral infection were tested in vitro on four human Ewing sarcoma cell lines. Notably evaluated were effects of the virus on the cell cycle and its replication efficiency. Within 24 h after infection, the synthesis of viral proteins was induced. Efficient H-1PV replication was confirmed in all four Ewing sarcoma cell lines. The cytotoxicity of the virus was determined on the basis of cytopathic effects, cell viability, and cell lysis. These in vitro experiments revealed efficient killing of Ewing sarcoma cells by H-1PV at a multiplicity of infection between 0.1 and 5 plaque forming units (PFU)/cell. In two of the four tested cell lines, significant induction of apoptosis by H-1PV was observed. H-1PV thus meets all the in vitro criteria for a virus to be oncolytic towards Ewing sarcoma. In the first xenograft experiments, however, although an antiproliferative effect of intratumoral H-1PV injection was observed, no significant improvement of animal survival was noted. Future projects aiming to validate parvovirotherapy for the treatment of pediatric Ewing sarcoma should focus on combinatorial treatments and will require the use of patient-derived xenografts and immunocompetent syngeneic animal models.
