Section des Unités de recherche
Report from the visiting committee
Research unit :
Cancer Virotherapy – UMR_S 701
University Louis Pasteur - Strasbourg 1
February 2008
Section des Unités de recherche
Report from the visiting committee
Research unit :
Cancer Virotherapy – UMR_S 701
University Louis Pasteur – Strasbourg 1
February 2008
Report from the visiting committee
The research unit :
Name of the research unit : Cancer Virotherapy
Requested label : UMR_S INSERM
N° in case of renewal : U701
Head of the research unit : M. Jean ROMMELAERE
University or school :
University Louis Pasteur – Strasbourg 1
Centre Allemand de Recherche sur le Cancer - DKFZ, University of Heidelberg
Other institutions and research organization :
INSERM
Date(s) of the visit :
February, 5th of 2008
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Members of the visiting committee
Chairman of the commitee :
Ms. Anna SALVETTI, Lyon
Other committee members :
Ms. Hildegard BÜNING, Köln, Germany
M. Jean DAVOUST, Paris
Ms. Gilliane CHADEUF, Nantes
CNU, CoNRS, CSS INSERM, représentant INRA, INRIA, IRD…
representatives :
M. Jean-Michel HEARD, Paris, CSS INSERM representative
Observers
AERES scientific representative:
M. François-Loïc COSSET
University or school representative:
None
Research organization representative (s) :
Ms. Christine TUFFEREAU, INSERM
Ms. Ruth WELLENREUTHER, DKFZ
Ms. Marie-Ange LUC, INSERM ADR de Strasbourg
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Report from the visiting committee
1 z Short presentation of the research unit
Total number of persons : 43
• Total number of scientists with permanent position : 8 (INSERM, CNRS and DKFZ)
• Number of postdoctoral fellows : 9
• Number of PhD students : 8
• Number of engineers, technicians and administrative assistants : 10
• Number of HDR : 4, all of them have PhD students
• Number of PhD theses completed in the past four years : 9 ; mean duration of 39 months
• Number of publishing scientists according to AERES criteria : 5 out of 8
2 z Preparation and execution of the visit
The overall quality of the written document was good. The only criticism concerned the lack of introduction on
parvovirus biology which made it difficult to fully appreciate the potential advantages of parvoviruses (PVs) compared
with other oncolytic viruses. The visit started in the morning by a general presentation of the Unit by the head of th
unit, followed by two specific presentations of teams 1 and 2. Each presentation was 20 min long and was followed by
25 min of questions in front of all the scientists who individually answered the questions. The morning sessions were
followed by a discussion in front of posters prepared by scientists, post-docs and PhD students. The quality of oral and
poster presentation was considered excellent by the committee members. The afternoon was dedicated to the
meetings with technicians/engineers, scientists, and students/post-docs. One of the committee members met the
technicians/engineers whereas the other members met the students/post-doc. All the members of the committee met
the scientists. During this meeting, each scientist was asked to present him/herself to indicate his/her position in the
Unit and his/her working conditions. A particular emphasis was given to the analysis of their publication record during
the last four years and to their status concerning the obtainment of the HDR.
3 z Overall appreciation of the activity of the research unit, of its
links with local, national and international partners
The Unit occupies a very specific research niche on oncolytic PVs. During the last four years the Unit has
followed its initial objectives that were:
1) to provide proof-of-concept of the anti-tumoural activity of rodent PVs ;
2) to decipher the molecular mechanisms used by PV to kill cancer cells ;
3) to improve the oncolytic activity of PV ;
4) to assess the clinical relevance of this approach for cancer therapy.
The Unit occupies a unique position as a French-German entity associated to INSERM and DKFZ, located in
Heidelberg, and as a member of the Canceropole Grand-Est. It is also intimately connected to the Heidelberg biopole,
the Heidelberg University Hospital and Strasbourg University and IRCAD Institute. From an international point of view,
this Unit represents one of the leading laboratories in Europe and abroad involved in the study of autonomous
parvoviruses and their applications as anti-tumoural agents. This specificity is also illustrated by its exceptional
position regarding the number of approved patents.
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4 z Specific appreciation team by team and/or project by
project
Team 1 : Development of new virus-based strategies and identification of novel targets for cancer therapy
Team 1 consists of 7 senior scientists (5 have permanent INSERM/DKFZ positions), 9 post-doc, 5 technicians and
5 students. It has published 29 articles, 8 reviews or book chapters, and 4 patents since its creation in 2004. The
research activities of this team cover nearly all the objectives defined by the Unit. The activity of this team has first
focused on the assessment of the anti-tumoural activity of PVs. Demonstration of the anti-tumoural properties of PV
infection was obtained in two models. In a rat model of transplanted glioma, the team provided evidence that PV
infection has the capacity to eradicate the tumour and to prevent relapse, without any obvious harmful effect on
normal surrounding tissues. This preclinical validation of PVs as anti-tumour agents, as well as the demonstration that
all human gliomas tested so far appeared susceptible to PV-induced lysis provide solid basis for the preparation of a
clinical trial in patients with glioma at Heidelberg University Hospital. A clinical protocol is currently being
elaborated, conditions for the preparation of clinical batches of PV have been set up, and a CRO is in charge of
organising the trial. In a rat model of pancreatic cancer, PV infection was shown to reduce tumour growth and to
improve recipient survival, especially when combined with chemotherapy. Further work is being done to confirm this
preclinical demonstration with the aim to conduct a second clinical trial in this indication in the near future. The
committee judged these works solid, convincing and promising, and encouraged the team to pursue efforts towards
clinical assessment in the two proposed indications.
The second objective of this team is to decipher the molecular mechanisms used by PVs to kill cancer cells.
Several mechanisms potentially accounting for the anti-tumour effect of PVs have been identified. The direct
cytotoxicity of PVs is related to specific biological activities of the viral protein NS1. This protein interacts with casein
kinase II, triggering a cascade of events leading to reorganisation of the cytoskeleton (ERM proteins, gelsolin)
favouring virus particle egress and release, altered expression of phospholipase A2, increased cathepsin activity in the
cytoplasm and cell death through apoptosis or necrosis. Studies supporting these conclusions are straightforward, well
conducted and demonstrative.
Although PVs do not induce strong inflammatory responses, it is nevertheless presumable that the observed
anti-tumoural action is at least in part mediated by immune responses. The team has performed several studies on
the induction of innate immune responses to PV infected tumour cells, especially on the role of interferon ß.
However, the activation of innate responses might be relayed by the initiation of adaptive responses mediated by
appropriately activated, tumour antigen-loaded dendritic cells. Adaptive responses against PV infected tumour cells
are likely responsible for the rejection of residual tumour cells, as illustrated by the observed anti-tumour vaccination
effect. Accordingly, the group coducted a collaborative work showing that PV-induced cell death enhances immune
response in vitro via increased cross-presentation by human dendritic cells. It would certainly be valuable to devote
more efforts on this question. This would create a bridge with clinical trials, the scope of which could be broadened
by immuno-monitoring the effects of oncolytic PV on the induction of anti-tumour B and T cell responses in enrolled
patients. It is suggested that the implication of an immunologist would strengthen the developments in this research
direction.
Several other projects of team 1 are aimed at improving the oncolytic properties of PVs and at extending the
use of PVs in other tumour models. They include combination with chemotherapy, targeting of histone deacetylase
inhibitors in tumours induced by human papilloma viruses, the use of shRNAs for the inhibition of key regulators, the
retargeting of PVs toward cell surface components specifically expressed at the surface of cancer cells, the
construction of hybrid viruses, using adenovirus vectors for the delivery of infectious PV genomes to tumours. These
multiple projects appeared at an early stage of development. Since each requires substantial investments, it is
suggested that the most promising ones are selected once results from preliminary studies are available, allowing
better focus on most competitive approaches.
Finally, an interesting project consists in the identification of new targets for anti-cancer treatment, using PVs
as baits. The distribution of SGTA, a housekeeping nuclear protein, is deeply modified by PV infection. SGTA knock
down induces cell mitotic arrest and kills tumour cells. Evidence was produced that SGTA contributes to correct
positioning of chromosomes during metaphase. BAG6 is a partner of SGTA. These two proteins and their interaction
are considered as potential targets for the development of anticancer treatments.
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Team 2 : Therapeutic validation of parvoviral vectors
Team 2 consists of 3 senior scientists (INSERM/DKFZ/CNRS), 1 guest scientist, 7 students and 3
engineers/technicians. This team has published 12 articles, 5 reviews or book chapters, and 2 patents since its
creation in 2004.
During the last four years the research activity of Team 2 was focused on the development of recombinant
parvoviral vectors encoding, in addition to the NS1 protein, either immuno-stimulating or anti-angiogenic agents. Most
notably, the team has achieved encouraging results in the demonstration of the anti-tumoural effect of MVM-based
parvoviral vectors coding for TNF and IP10, in a mouse glioma model. However, the development of such vectors is
hampered by a defect in infectivity as compared to the wild type virus. This will certainly require extensive
biotechnological developments in order to be able to achieve higher infectious titres. Some specific analyses are
already envisioned to solve this problem including, notably, the comparison of capsid structures of wild type and
recombinant MVM particles. The second main project of this team was to assess the safety of PVs in the brain and to
study the interaction between microglia and glioma cells. The first part of this study has provided essential results
demonstrating that PVs are not toxic for normal brain cells. Studies are now underway to elucidate the mechanisms
responsible for microglia-induced killing of glioma cells. Finally, a third project of team 2 consists in the search for
viral and cellular determinants of cell permissiveness to parvovirus infection. This includes generation of chimeric
MVM/H1 parvoviruses and analyses of cellular genes modulating PV infection. All together, these projects fit in the
research activities of the Unit and are potentially important to provide new tools and insights for a more extensive
use of PVs in cancer therapy. However, the adjustment between the projects and the human resources should be
carefully examined. In particular, the team, which has lost two tenured scientists in the past four years, should
consider hiring some experienced post-docs to strengthen all the projects related to parvoviral vectors development.
In its current state, it is recommended that the team focus its efforts on some essential points to be able to
significantly advance in this field.
5 z Appreciation of resources and of the life of the research unit
•
Human resources :
Because of its bi-national nature the Unit has attracted many scientists and students from both nationalities. It
also includes a large number of students and post-docs coming from many other countries. Within the last four years,
a strong effort has been put in the recruitment of post-docs that actually constitute a very important part of the Unit
(especially of team 1). As many other Units, there is a critical lack of technicians and administrative given the number
of individual projects that are presently conducted and the development of a clinical trial.
•
Materials and financial resources :
The Unit is located in Heidelberg, within DKFZ (660 m2) and Strasbourg, at IRCAD (188 m2). It benefits from all
infrastructures provided by both Institutes and surrounding campuses. From the financial point of view, the Unit has
obtained during the last four years competitive grants and/or fellowships from German (von Humboldt Foundation,
DKFZ), French (INCA, Cancéropôle Grand-Est) and international organizations (EMBO) that can fully support all its
research activities.
6 z Appreciation of the life in the research unit
The meeting with the personnel of the Unit, including scientists, post-docs, students and
technicians/engineers, showed that human relationships among all lab members are in general very good. Students
are enthusiastic about the scientific interactions in the Unit and the Institute. There are several meetings and
seminars organized within the Unit and DKFZ at which each member actively participate. The PhD students are asked
at least once a year to present their result during department seminars. However, despite the existence of several
scientific collaborations between individual team members, the committee felt that the large number of projects
tended to split the two teams into several subgroups which is not favourable for creating a common strategic project.
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7 z Recommendations and advice
•
Strong points :
The committee members agreed that the Unit performs a very good research. They particularly appreciated
the fundamental projects developed on parvovirus biology notably on aspects related to their tumour-specific
cytotoxic effects and the development of novel synthetic targets for cancer therapy.
The in vivo studies concerning the PVs anti-tumoural effects, in combination or not with chemotherapy, were
also considered as very important in view of clinical applications.
The committee also appreciated the number and quality of patent applications and considered that the Unit
holds a unique worldwide position with regards to the development of PVs as anticancer agents.
•
Recommendations :
Given that the current Research Director will be retiring in six years, the committee estimates that it would be
worth that tenured scientists in the Unit, together with the Research Director, start to develop a strategic plan for
the future. Plans might include remodelling of the Unit with respect to teams and team leaders in order to focus on
the most critical projects.
The committee suggests that, in this context, the Unit considers the creation of a third team focusing on the
analysis of the interactions between PV infected tumour cells and the immune system. Ideally, this could imply the
recruitment of an experienced immunologist.
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