Oncolytic parvovirus H-1 clinical trials: accompanying research

Group leader: Assia L. Angelova, PhD

Contact:

Assia Angelova, PhD

Tel. +49 6221 42 49 64
Fax +49 6221 42 49 62
Email: Assia Angelova

The concept

Research conducted by the CANCER VIROTHERAPY team focuses on viruses belonging to the Parvoviridae family. The research program is based on the ability of certain protoparvoviruses (PV) to prevent the formation, inhibit the growth and cause the regression of various cancers in animal models. Previous work of the group showed that these oncosuppressive properties rely, at least in part, on the preferential multiplication of PV in certain tumors (oncotropism) and on the cytopathic effects they exert (oncolysis). Furthermore, innate and adaptive immune responses contribute to the anticancer activity of PV. The program exploits these experimental evidences so as to address issues directly related to PV clinical applications. Besides pursuing preclinical evaluation of PV antitumor activity, the team is endeavoring to support translation to bedside through a clinical trial-accompanying research platform.

Glioblastoma is the most aggressive human primary brain tumor, characterized by inevitable recurrence and median survival of less than 15 months after initial diagnosis. Current treatment options do not achieve a major improvement, and the prognosis for glioblastoma patients still remains very poor. Preclinical research performed in the Tumor Virology Division has demonstrated that the oncolytic H-1 parvovirus (H-1PV) exerts striking oncotoxic and oncosuppressive effects in glioblastoma in vitro and in vivo models. 

In 2011, a phase I/IIa clinical trial (ParvOryx01) was launched (sponsored by Oryx GmbH, Baldham, Germany) with the aim to evaluate the safety, tolerability and efficacy of H-1PV therapy in patients with recurrent glioblastoma. This was the first clinical trial with a replication-competent oncolytic virus in Germany, and the first one to involve an oncolytic parvovirus. Patients were subjected to either intratumoral or systemic H-1PV administration, followed by tumor resection nine days after treatment and repeated virus application into the walls of the resection cavity. Together with the promising clinical observations, several intriguing findings arose from the in situ analyses of resected glioblastomas:

  • viral mRNA synthesis and protein expression in H-1PV-injected tumors
  • virus expression at tumor sites distant from the injection site
  • H-1PV ability to cross the blood-brain/tumor barrier and penetrate the tumor after systemic virus administration, and
    • intratumoral necrosis, microglia/macrophage activation and accumulation of activated cytotoxic T cells, hinting at immunogenic conversion in the glioblastoma microenvironment 

The outcome of the ParvOryx01 trial has been recently published (for a reference, see Geletneky et al., Molecular Therapy 2017) and provided strong impetus for further H-1PV clinical development. In 2015, a second clinical trial (ParvOryx02) was launched, and is still in progress, in inoperable metastatic pancreatic cancer patients. In addition, compassionate parvovirus uses in brain, lung and gastrointestinal cancer patients are currently ongoing. Our group is responsible for the research accompanying both the ParvOryx02 trial and the compassionate H-1PV uses.

Our main trial/compassionate use-accompanying research activities include:

  • detection of H-1PV replication and expression markers in patient-derived tumor material using fluorescence in situ hybridization (FISH), immunofluorescence and immunohistochemistry
  • analysis of H-1PV intratumoral distribution after local and systemic virus administration
  • phenotypic characterization of  H-1PV target cells within the heterogeneous tumor cellular environment
  • analysis of tumor microenvironment, including tumor infiltration with immune cells, evaluation of their activation status and assessment of tumor-associated microglia/macrophage pro-inflammatory (M1) polarization 

We believe that further preclinical and clinical trial-accompanying studies on markers of H-1PV cytotoxicity and immunostimulating effects will warrant the development of H-1PV-based combinatorial treatment protocols, the extension of parvovirus clinical studies to subsequent phases and to additional tumor entities.

Team members:

Prof. Jean Rommelaere, PhD
Assia L. Angelova, PhD
Karsten Geletneky, MD
Alexandra Just 
Milena Barf

Collaborations:

Prof. Dr. Andreas Unterberg, Department of Neurosurgery, Heidelberg University Hospital
Dr. Albrecht Stenzinger, Department of Pathology, Heidelberg University Hospital
Prof. Dr. Andreas von Deimling, Department of Neuropathology, Heidelberg University Hospital
Prof. Dr. Volker Daniel, Institute of Immunology, Heidelberg University Hospital
Prof. Dr. Dirk Jäger, Department of Medical Oncology, National Center for Tumor Diseases (NCT), Heidelberg 
Dr. Guy Ungerechts, Department of Translational Oncology, NCT, Heidelberg

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