Development of a novel combination therapy based on oncolytic parvovirus H-1PV and the BH3 mimetic ABT-737 against glioblastoma

  • Marchini, Antonio (PI)

    Project Details


    The H-1PV parvovirus is not pathogenic in humans, and its oncolytic and oncosuppressive properties have been demonstrated in vitro and in vivo. A phase I/IIa clinical trial in patients with glioblastoma showed that H-1PV treatment is safe and well tolerated, and provided first evidence of efficacy. However, the wild type virus was unable to eradicate the tumour, indicating that the treatment needs further development to improve the clinical outcome.One of our major goals is to develop combination protocols that enhance the anticancer potential of H-1PV while preserving its excellent safety profile in normal tissues.
    We previously showed that the BH3 mimetic ABT-737 boosts H-1PV oncolysis in a synergistic manner in vitro (35 cancer cell lines) and in vivo (rat model of human pancreatic carcinomas). We also showed that it restored the ability of the virus to trigger apoptosis in glioma cells. Based on these promising results, we submitted a grant proposal to Télévie in 2017 with the following goals: (i) to characterize the cell death mechanisms activated by H-1PV/ABT-737 co-treatment and (ii) to validate the anticancer activity of the new therapy in clinically relevant animal models of human gliomas. This was a two-year research project, but only one year was financed by Télévie. To complete our promising work, we are requesting a one year extension of funding.
    In the first year of our project, we further substantiated that H-1PV/ABT737 is a valid treatment against gliomas. We characterized the cell death mechanisms of this co-treatment in glioma cell lines. The co-treatment induces oxidative stress via reactive oxygen species (ROS) accumulation,which disturbs various cellular organelles, including the mitochondria, lysosomes, and endoplasmic reticulum. Remarkably, H-1PV/ABT-737-induced cell death was associated with elevated intracellular Ca2+ release, increased surface exposure of calreticulin, enhanced secretion of HMGB1, and ATP release, all of which are typical determinants of immunogenic cell death. These results indicate that H-1PV/ABT737 co-treatment not only directly induces more potent oncolytic activity but also may increases the anti-tumour immune response compared with single treatment.
    Furthermore, first validation in U87 xenograft immunodeficent rat models of human gliomas confirmed that ABT-737 strongly enhances H-1PV oncosuppression when single treatment was ineffective (P <0.001) (paper inpreparation).
    In the second year of this research program, our goal is to investigatewhether H-1PV/ABT-737 co-treatment triggers anticancer immune responses in an immunocompetent rat model of glioma. This will provide the basis for moving this new combination therapy into the clinic.
    AcronymH-1PV/ABT-737 combination against glioma
    Effective start/end date1/10/1930/09/20


    • FNRS - Fonds National de la Recherche Scientifique: €136,756.00
    • FNRS - Fonds National de la Recherche Scientifique: €58,878.00


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