Table of Contents
Head: Prof. Jean Rommelaere
Research at the CANCER VIROTHERAPY Unit focuses on viruses belonging to the parvovirus family. These prefer to multiply in dividing tumor cells. By doing so, they can inhibit tumor growth by directly causing the tumor cells to die or making them more receptive to various therapeutic treatments. Our effort is to understand the underlying mechanism of this effect. Due to their preference for tumor cells, parvoviruses also make good vehicles for gene therapy. Thus, we use them as vectors for carrying specific therapeutic genes to cancer cells. These vectors are further refined in order to achieve a higher effectiveness in the gene therapy of tumors.
The research progam is based on the ability of certain autonomous parvoviruses (PV) to prevent the formation, inhibit the growth, or cause the regression of cancers. These oncosuppessive properties rely at least partly on the preferential multiplication of PV in certain tumours (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 experimental systems that have been developed in the Unit so as to address issues directly related to clinical applications of PV. Part of the program is focused on basic scientific investigations aiming at understanding the molecular mechanisms of PV cytotoxicity and immune-modulation, which will allow the optimization of therapeutic PV (vectors). Since the PV life-cycle and cell physiology are highly interdependent, investigation of the cytopathic effects of PV is leading to the discovery of new cell functions that might be appropriate targets for non-conventional anticancer therapies based on PV or their derivatives/analogues. This research thus opens original prospects for the development of anti-cancer toxins and vaccines. Moreover the program involves (i) the preclinical evaluation of the antitumour activity of PV and of vectors or products obtained with the help of PV, and (ii) the transposition of the most advanced candidates to a clinical setting.
In the framework of collaborations established between the Unit and various experts, preclinical research will focus notably on the use of wild-type PV to circumvent cell mechanisms of resistance to conventional anticancer treatments, and on the use of PV vectors as adjuvants in certain cancer immunotherapy protocols.
Five main focuses of research are currently developed:
- Clinical research: implementation and biological monitoring of a phase I/IIa clinical trial of parvovirus H-1 (H-1PV) in glioblastoma patients (in cooperation with the Dpt. of Neurosurgery/Univ. Hosp. Heidelberg [K.Geletneky], and ORYX GmbH & Co. KG).
- Production of preclinical proofs of concept for future clinical applications: (i) assessment of the oncosuppressive capacity of H-1PV against Pancreatic Ductal AdenoCarcinoma (Z.Raykov, C. Dinsart; in cooperation with the European Pancreatic Center/Univ. Hosp. Heidelberg, and the First Dpt. of Internal Medicine/Univ. Hosp. Mainz) and pediatric tumors of the nervous system (J. Lacroix; in cooperation with the Dpt. of Pediatric Hematology and Oncology/Univ. Hosp. Heidelberg); (ii) search for tumor entities and individual signatures that are predictive of responsiveness to parvovirus therapy (A. Marchini, C. Dinsart, J. Lacroix).
- Basic investigation and optimization of the molecular mechanisms by which PV kill tumor cells and stimulate anticancer immune responses: (i) interference of PV with cytoskeleton dynamics and cellular metabolic pathways leading to cytostasis and (immunogenic) cell death. (J. Nüesch, A. Marchini, Z. Raykov); (ii) generation and/or isolation of PV variants endowed with enhanced oncolytic or adjuvant capacity (J. Nüesch, Z. Raykov); (iii) assessment of combination therapies using PV together with other viruses or chemical modulators of gene expression (A. Marchini, J. Lacroix).
- Basic investigation and optimization of cell permissiveness for PV replication: (i) production and analysis of viral variants showing an enhanced capacity for intracellular trafficking and spreading (C. Dinsart, J. Nüesch, N. Salomé); (ii) improvement of PV uptake into tumor cells through capsid engineering or production of chimeric viruses (A. Marchini).
- Validation of recombinant parvoviral vectors in anticancer therapies: attempts at reinforcing intrinsic PV oncosuppression through virus arming with transgenes encoding immunostimulating cyto/chemokines and anti-angiogenic polypeptides (C. Dinsart).