The Laboratory of Oncolytic-Virus-Immuno-Therapeutics (LOVIT) is a joint research Unit between the Luxembourg Institute of Health (LIH) and the DKFZ established in 2017 to advance research on oncolytic virus immunotherapy.  LOVIT is headed by Antonio Marchini and presently includes three post-docs and two technical assistants working in Heidelberg and/or Luxembourg  laboratories.

LIH Homepage

Our Vision

Our mission is to fight cancer. Our major goal is to develop novel anticancer therapies based on oncolytic parvoviruses which are efficient, specific and safe. We are committed to excellent science conducted rigorously but with great enthusiasm. To achieve our goals we will create a supportive environment that promotes positive interactions and cooperation between Team members, built on the reciprocal respect of each individual personality. Our motto is: we will do our best but there is always room for improvement.

Marchini’s Team

From left: Dr. Amit Kulkarni (post-doc, Sep. 2011-date), Simone Müller (M.sc student), Dr. Anna de Oliveira (post-doc April 2012-date), Ann-Christin Gnirck (M.sc student), Dr. Junwei Li (post-doc, May 2008-date), Lisa Rausch (M.sc student), Tiina Marttila (TA, 2008-date), Dr Antonio Marchini (PI since June 2006), Annabel Grewenig (TA, 2014-date).
© Tom Holz (t.holz@dkfz.de)

Current Research

Fig. 1. The Ad-PV chimera strategy. The entire oncolytic parvovirus genome (PV, in black) was inserted into a replication-defective Adenovirus genome (Ad, in red). The chimera proved able to effectively deliver the PV genome into cancer cells, from which progeny PV particles were generated, induced cell lysis and infected neighboring cancer cells.
© dkfz.de

Oncolytic viruses (OV) are attracting growing interest as cancer therapeutics because they specifically kill cancer cells and activate antitumor immune responses (1). Our research mainly focuses on oncolytic rat parvovirus H-1 (H-1PV). H-1PV is not pathogenic for humans and possesses oncolytic and oncosuppressive properties (2, 3). H-1PV has been tested in a phase I/IIa trial in patients with recurrent glioblastoma, the most common and aggressive form of brain tumour in humans. Results show that virus treatment is safe, well tolerated and associated with first evidence of efficacy. However, the virus alone under the regimes used was unable to eradicate the tumour in patients. Further development of H-1PV is therefore required in order to improve clinical outcome.

 

To this end, at a translational level we are actively working on the construction of second generation of PV-based vectors with improved oncosuppressive activity and in the design of novel combination therapy based on PV and other anticancer agents (see below).  Moreover, on a more basic level, we devote special efforts in the characterization of PV life cycle and we have identified several cellular factors that may be important for virus entry, transduction and cytotoxicity. These factors could be potentially used either as cellular markers to predict the responsiveness of individual tumours to parvovirus treatment and/or as a mean for the development of novel PV-based therapies with enhanced anticancer efficacy.

 

Translational projects

Using pancreatic carcinomas and gliomas as tumour models, we are using different complementary strategies to develop second generation PVs and PV-based treatments. In particular we were successful in:

 i)  the construction of innovative oncolytic viruses: retargeted PVs (4), chimeric vectors of adenovirus-PV genomes (5), PVs expressing sh/miRNAs (6); 

ii) design and assessment of novel combination therapies using PVs together with other anticancer agents achieving strong synergistic anticancer activity with apoptosis inducers (7), and/or epigenetic modulators of gene expression (8). These results warrant clinical evaluation of these combination treatments.

In particular the research program of LOVIT builds on our recent pioneering studies (3).  We have developed a first generation of Ad-PV chimeras in which an engineered version of the H-1PV genome was inserted into the Ad5 genome. The Ad carrier serves as a Trojan horse to efficiently bring the PV-genome into cancer cells, where the PV DNA gets excised from the Ad backbone and initiates a genuine PV cycle in an autonomous way. As a result, the chimeras were shown to be able to specifically infect and kill cancer cells by their cytolytic activity and to produce PV particles able to invade and further propagate into neighboring cancer cells inducing secondary rounds of lytic infection (Fig. 1).  The Ad-PV chimera represents an innovative anticancer agent that can be further improved (e.g. through arming with therapeutic transgenes) and/or combined with other anticancer modalities (e.g. immunotherapy) to enhance antitumour potential.

The construction of second generation chimera and the rational design of PV or Ad-PV chimera based combination strategies are the main goals of LOVIT.  Our ambition is to produce the necessary proof(s)-of- concept necessary to move most promising therapies from the bench into the clinic.

Basic projects

We discovered that H-1PV through its non-structural protein NS1 induces intracellular accumulation of reactive oxygen species (ROS) leading to DNA damage, apoptosis and lysis of cancer cells (9). We are interested in further characterizing H-1PV-mediated cancer cell death.

Furthermore, we aim to identify cellular markers that predict the responsiveness of individual tumors to parvovirus treatment. This project is based on our previous results (from a high throughput siRNA library screening), the validation of which will therefore be a milestone for our laboratory. These studies will shed light on the cellular determinants of cancer cell permissiveness for parvovirus infection, and on the mechanisms underlying PV cytotoxicity, a necessary step towards personalized parvovirus therapy. We anticipate that the knowledge gained through this research will also be pivotal for the development of innovative PV silencer and armed Ad-PV vectors that are able to condition the tumor intracellular milieu so as to improve PV replication and anti-cancer efficacy.

References and selected publications:

1.         Marchini, A., Scott, E. M., and Rommelaere, J. (2016) Overcoming Barriers in Oncolytic Virotherapy with HDAC Inhibitors and Immune Checkpoint Blockade. Viruses 8

2.         Marchini, A., Bonifati, S., Scott, E. M., Angelova, A. L., and Rommelaere, J. (2015) Oncolytic parvoviruses: from basic virology to clinical applications. Virol J 12, 6

3.         Nuesch, J. P., Lacroix, J., Marchini, A., and Rommelaere, J. (2012) Molecular pathways: rodent parvoviruses--mechanisms of oncolysis and prospects for clinical cancer treatment. Clin Cancer Res 18, 3516-3523

4.         Allaume, X., El-Andaloussi, N., Leuchs, B., Bonifati, S., Kulkarni, A., Marttila, T., Kaufmann, J. K., Nettelbeck, D. M., Kleinschmidt, J., Rommelaere, J., and Marchini, A. (2012) Retargeting of rat parvovirus H-1PV to cancer cells through genetic engineering of the viral capsid. J Virol 86, 3452-3465

5.         El-Andaloussi, N., Bonifati, S., Kaufmann, J. K., Mailly, L., Daeffler, L., Deryckere, F., Nettelbeck, D. M., Rommelaere, J., and Marchini, A. (2012) Generation of an adenovirus-parvovirus chimera with enhanced oncolytic potential. J Virol 86, 10418-10431

6.         Illarionova, A., Rommelaere, J., Leuchs, B., and Marchini, A. ( 2014) Modified parvovirus useful for gene silencing. European Patent 2620503

7.         Li, J., Schroeder, L., Geletneky, K., Rommelaere, J., and Marchini, A. (2016) Cancer therapy with a parvovirus combined with inhibitors of the anti-apoptotic Bcl-2 proteins. European Patent 3024491

8.         Li, J., Bonifati, S., Hristov, G., Marttila, T., Valmary-Degano, S., Stanzel, S., Schnolzer, M., Mougin, C., Aprahamian, M., Grekova, S. P., Raykov, Z., Rommelaere, J., and Marchini, A. (2013) Synergistic combination of valproic acid and oncolytic parvovirus H-1PV as a potential therapy against cervical and pancreatic carcinomas. EMBO Mol Med 5, 1537-1555

9.         Hristov, G., Kramer, M., Li, J., El-Andaloussi, N., Mora, R., Daeffler, L., Zentgraf, H., Rommelaere, J., and Marchini, A. (2010) Through Its Nonstructural Protein NS1, Parvovirus H-1 Induces Apoptosis via Accumulation of Reactive Oxygen Species. J Virol 84, 5909-5922

Collaborations:

Gudrun Rappold, University of Heidelberg, Heidelberg

Laurent Brino, IGBMC, Strasbourg, France

Peter Krammer, DKFZ, Heidelberg, Germany

Guy Ungerechts and Cristine Engeland, NCT, Heidelberg, Germany

Simone Niclou, LIH, Luxembourg

Funding (2000-2017):

Support to AM as PI byUniversity of Heidelberg, Eli Lilly International Foundation, EMBO, Alexander von Humboldt-Foundation, German Cancer Research Center, French National Cancer Institute (INCa), Deutsche Krebshilfe, Oryx GmbH, Luxembourg Cancer Foundation, Télévie, for more than 3.3M €.

to top