Section des Unités de recherche Report from the visiting commitee Research unit: Biothérapies hépatiques University of Nantes January 2008
Section des Unités de recherche Report from the visiting committee Research unit : Biothérapies hépatiques University of Nantes January 2008
Report from the visiting committee The research unit : Name of the research unit : Biothérapies hépathiques Requested label : (UMR, UPR, EA) : UNIT-M N in case of renewal : Head of the research unit : Nicolas Ferry University or school : Nantes University Other institutions and research organization: CIC04 : Centre d investigation clinique de Nantes Date(s) of the visit : 25 January 2008 2
Members of the visiting committee Chairman of the commitee : Mme Hélène GILGENKRANTZ, Institut Cochin Other committee members : M. Peter F. SEARLE, University of Birmingham, UK M. Bruno SANGRO, Pamplona, Spain Mme Anne DUBART-KUPPERSCHMITT, Institut Cochin CNU, CoNRS, CSS INSERM, représentant INRA, INRIA, IRD..) representatives : Mme Christine PERRET Observers AERES scientific representative: M. Pierre BEDOSSA University or school representative: M. Jacques GIRARDEAU Research organization representative (s) : Mme Josiane POGGIOLI 3
Report from the visiting committee 1 Short presentation of the research unit Numbers of lab members including researchers with teaching duties, full time researchers, ingeneers, PhD. students, technicians and administrative assistants : 21 Numbers of HDR and of HDR who are PhD students advisors : 5 Numbers of PhD. Students who have obtained their PhD and average lenght of a PhD during the past 4 years : 2 Numbers of PhD students currently present in the research unit, number of PhD students with fellowships : 5 Number of «publishing» lab members : 10 2 Preparation and execution of the visit The visit was 1 day long. Morning session included presentations of the different scientific projects by senior researchers. Afternoon session was devoted to on-site visit and poster presentation by students. The committee was impressed by the quality both of the written document and of the oral presentations performed by each of the four project leaders. The fruitful ongoing scientific discussions were also greatly appreciated. Besides the head of the proposed research unit, the group includes two young and dynamic investigators and one team director coming back to France after 10 years in UK, all three of them having been recruited to the team within the last two years. The organisation of the visit also provided time for a separate discussion with students. 3 Overall appreciation of the activity of the research unit, of its links with local, national and international partners The committee particularly commends the overall coherence of the presented project with two distinct but interconnecting parts (see specific appreciation project by project) using common technical tools, vectors and approaches. Therefore, two different expertises have been very recently put together, one concerning the development and modification of viral vectors and the other concerning the use of innovative gene therapy and imaging approaches for liver cancer. This recent association of 4 researchers including two research directors occurs in the context of a very favourable technical and scientific environment in Nantes (Centre d Investigation Clinique, central facilities for production of viral vectors and clinical grade cells, an internationally recognized Immunology INSERM 601 Unit in the same building and the veterinary centre devoted to gene therapy experiments on big animals including non human primates in Boisbonne). They have developed collaborations with a French team also working on liver gene therapy on monkeys. Therefore, their involvement in local and national networks is excellent. There are also international collaborations for specific projects with groups in the Netherlands, UK and USA. It will be important in the future to develop international networks particularly in the view of potential European funding. 4
4 Specific appreciation team by team and/or project by project Project 1: Gene therapy of Crigler-Najjar disease and lentiviral vectors for treating inherited metabolic disorders This part of the team has a long past activity and expertise on gene therapy approaches for liver diseases or metabolic disorders. The main aim of the project is to enhance the efficacy in order to go into clinical trials. The group has been reinforced by the recent arrival of a young promising investigator who already published on the project in 2007 and has acquired a very good knowledge on lentiviral vectors during his post-doc in an internationally recognized laboratory. Strength of the project: Recognized expertise of the team both on the clinical aspects of the disease and on the technological aspects of vectors used. Presence of large animals technological platform for gene therapy assays offering the opportunity to perform primate studies in excellent conditions. Very few teams in Europe are able to perform such kinds of experiments. Potential advantages of the scaav, with encouraging preliminary results and collaboration with group in Amsterdam Collaboration with another group for the lentiviral gene therapy approach of another metabolic disorder in a consortium context. Originality of the lentiviral vector modification approaches (non-integrative, micro-rna, alternative envelope proteins) and the development of alternative, improved protocols for administration. ANR and AFM financial support in adequation with the project. Globally these different items are guarantees of the feasibility of the project. Weakness of the project: A rate of publication in the good range for the number but non in outstanding range for their impact factor even if they are within the best in the gene therapy field (Mol Ther, Gene Ther, J Gene Med, J Hepatol) in the last three years. Crigler Najjar is a very rare disorder. However, if some proposed strategies enhance the efficiency of gene transfer, they could also be applied to other metabolic diseases Numerous vectors and numerous strategies to be tested for a small group. Focusing on the more promising or original ones would probably be more efficient for maintaining and enhancing international competitiveness. An effort to create an European consortium to test the different modified vectors in equivalent conditions should be appreciated Project 2: Biotherapy of Hepatocellular Carcinomas This project develops two strategies for therapy of liver cancer, one immunological and the other based on the NIS gene for imaging oncolytic viruses, with potential for targeted radiotherapy. Both are based on projects previously led by the research director in London, and both lead towards potential clinical trials in patients with HCC. The immunology project will be the particular focus of a recently recruited junior investigator who has already published on the project. 5
Strengths of the project: Arrival of a new research director with the expertise in the field particularly of NIS as a non-invasive imaging tool and LLO-expressing E.coli as a vector for cancer vaccines. Originality of some combined approaches for example using CIK cells and oncolytic vectors or to use NIS both as an imaging tool and an inducer of cell death with strong rationale behind the proposed strategies. The committee appreciates a couple of nice and elegant tools developed in this project Facilities of the technological platforms available particularly for imaging (pet-scan available for rodents), and the advantages of the vector- and cell-facilities for preclinical development and clinical trials. Promising preliminary results with LLO-Ecoli/tumour antigen in mice and interesting scientific data regarding effects on regulatory T cells. Already ongoing clinical trial in HCC immunotherapy provides valuable experience of the pathway from bench to clinics Good range of recent publications (J Immunol, Cancer Res, Mol Ther, Gut ) in the last two years Weakness of the project: Potential risk that simultaneous work with too many vaccine vectors for AFP immunotherapy could slow progress and impede competitiveness for a small group Vaccinia vector may be too premature to be considered for clinical applications Possibility that new drugs (such as Sorafenib) could make it more difficult to establish gene therapy clinical trials. Combining different approaches remains possible. Intellectual property: the lack of patents covering any of the aforementioned gene transfer vectors although they would be likely to facilitate clinical development. Specific Remark: No specific project has been presented by one of the researcher who has only temporarily joined the team and who will develop his own research team in the future. However, as an hepatologist, he will be involved in the discussion for clinical aspects of the project. 5 Appreciation of resources and of the life of the research unit Of the quality of the management : Very good interactions between both groups and also between the research team and clinicians Of human resources : A good match between the number of students and researchers for the projects proposed; A good combination between MD and scientist students. Potentially difficulty in the next years to obtain financial support for PhD (only 1 doctoral school in the university). All PhD have private or associative funding. Of the communication strategy : One lab meeting per week in which students are presenting their own data and results. One meeting per week in the IMAD context and external meeting once a month. 6
6 Recommendations and advice Strengths : A young and dynamic team with a complementary expertise put together to enhance the panel of tools available for liver gene transfer either for metabolic disorders or hepatocellular carcinoma. It seems to the committee that the presented project harbours innovative and original tools in a combination with an excellent technological environment offering all facilities to ascertain the feasibility of the project even in this competitive field. The possibility to perform preclinical studies on large animals such as non human primates and imaging the distribution of the vectors for cancer are clear strengths of the project. The considerable synergy between the expertises of the investigators and the different projects provides strong potential to increase competitiveness, and is likely to lead to significant informative clinical trials. Weaknesses : The level of publications could ideally be in higher rank journals Recommendations : would be to pay attention to the benefits of patenting and define a clear line of priorities for the development and modifications of vectors and strategies. Due to the youth of some investigators, the number of vectors and strategies to develop seem sometimes to the committee not completely realistic regarding the number of people involved in each project. The PI should therefore put the priority to some of them. Global conclusion : This new group is in a strong promising position to undertake a useful programme of preclinical studies, leading probably to important, informative clinical trials. 7