M Thierry

Alex Duval

Ian Tomlinson

M Efthimios

M C Skoulakis

Ms Valérie Cormier

Jean Rosenbaum

M Cafer

Ms Nicole Orange

Ms Chantal Lasserre

M Hubert

Ms Virginie Charmoy

M Bernard Daumur

Dean Pierre Freger

M Pierre

The visit was organized on November 23rd 2010. After a general presentation of the unit, Thierry FREBOURG, Jean-Michel FLAMAN and Jean-Baptiste LATOUCHE presented the cancer genetics project then Thierry FREBOURG, Magalie LECOURTOIS and Alexanda MARTINS presented the neurogenetics projects. After meeting with the institutional representatives, the site committee splitted into three subgroups to meet with PhD students, engineers and technicians and researchers. The visit ended with a closed deliberation of this committee.

 History and geographical localization of the research unit, and brief presentation of its field and scientific activities

The new unit is a joint structure between INSERM and the University of Rouen and is in direct continuity with the previous unit. The clear scientific unifying criteria for the unit is human genetics with two groups, one on cancer genetics and the other on the genetic bases of neuropsychiatric diseases. The unit has a very strong structural role for biomedical research, both in Rouen and more widely in the region Normandie. It is expected to be a major partner in the forthcoming Institute for Research and Biomedical Innovation of Haute Normandie.

 Management team

Each group includes different projects that are conducted either by the group leaders themselves or by permanent scientists. In addition, each project includes clinician-scientists that enable a very tight link with the hospital. The director is assisted by a secretary. The whole laboratory appears as very united, using and exchanging on concepts and methodologies in genetics. Group and lab meetings are organized on a weekly basis.

 Staff members (on the basis of the application file submitted to the AERES) 2  Overall appreciation on the research unit

 Summary

The Unit is composed of two teams. Team n° 1 : Genetics of cancer headed by Thierry Frebourg develops a project on genetic basis of colorectal cancer, the Li and Fraumeni syndrome, immuno-therapy of colorectal cancer and responses to therapy in colorectal cancer. Team n° 2 : neurogenetics headed by Dominique Campion addresses topics on the genetic basis of dementia with a particular emphasis on Alzheimer disease, use of Drosophila to investigate mechanisms of neuronal cell death, SMA and splicing, CNV and mental retardation and psychosis. The unit has contributed to important developments and findings in the last four years. Of particular note are the development of ex vivo splicing assays that are used by both groups, the progress in understanding the molecular bases of Li-Fraumeni syndrome, hereditary colorectal cancer and Alzheimer disease, the search for causal CNVs in mental retardation and psychoses, the use of Drosophila as a model system to investigate neurodegenerative diseases.

 Strenghts

-Excellent integration in the medical community. In addition to the principal investigators of the project, a total of 12 physicians are partners of the unit and involved in the projects. They bring to the unit critical clinical expertise.

-Excellent expertise of the group leaders in human genetics, cancer and neurodegenerative disorders -Strong interest of the unit in technological developments and valorization. Some tools developed by the unit are used by many French laboratories (QMPSF technique, Alamut software…).

-Specific interest in mutations generating splicing defects, which clearly constitutes an originality in the French genetic landscape.

-International visibility in studies of Li-Fraumeni syndrome and Alzheimer disease. -Well-organized continuum between research, molecular diagnostic and the clinics.

-Development of a strong partnership with the cancer genetics unit in Caen.

 Weaknesses

-Some projects do not have a sufficient critical mass, or the appropriate environment to be really competitive at the international level.

 Threats -There is a risk of dispersion due to the number of projects -The difficult choice between genetic projects, which require a strong investment in bioinformatics and a scaling up of the cohort of patients, and functional investigations of the identified mutations.

 Recommendations

-To scale up some genetic projects -To encourage permanent scientists who are not group leaders to take the lead on some projects and consequently to publish as senior authors.

-To define a clear strategy for the creation of new groups, being either headed by scientists of the unit as emerging group leaders, or attracted from the outside.

-Question the follow-up of the immunotherapy and anti-EGFR sensitivity programs -Put emphasis on the functional characterization of mutations suspected to alter splicing.

-Should Drosophila be the model system to be prioritized for functional analyses of variants, this team should be reinforced.

Consider electrophysiology as a complementary system. Strong examples in the cancer genetics field are:

-The study of the genetic interaction between MDM2 and p53 in Li-Fraumeni syndrome.

-The update of the clinical criteria for Li-Fraumeni syndrome.

-The contribution of germline rearrangements to the spectrum of BRCA2 mutations.

-The relevance of KRAS mutations for the management of colorectal cancer patients.

-The characterization of BRCA1, BRCA2, MLH1, MSH2 unclassified variants for splicing effect.

-The role of p53 mutation to predict response of colorectal cancer to Cetuximab therapy.

Strong examples in the neurogenetics field :

-Identification of APP locus duplication in early onset Alzheimer disease which clearly constituted a major breakthrough in Alzheimer disease research. The princeps paper has been followed by a comprehensive characterization of the clinical and pathological features of APP-duplication linked Alzheimer disease.

-Association of a PRODH CNV with autism -Identification of cytoskeleton proteins as potential modulators of Tau-induced neurodegeneration in Drosophila.

-The study and characterization of the genetic interaction between SMN1 and SMN2 variants.

In addition to these scientific contributions, it is important to mention that the unit has developed technological or bioinformatic tools (QMPCF, Alamut) that are widely used internally but also more broadly by the scientific community in France.

The unit seems to have a strong collaboration with a local bioinformatics group. The unit has recently applied to the EQUIPEX call with the aim to develop bioinformatics tools to be used for NGS analysis. If not granted it is not clear what will be the plan B for NGS analyses.

Importantly, the unit has also been directly involved in the creation of three start-ups.

 Appreciation on the impact, the attractiveness of the research unit and of the quality of its links with international, national and local partners

The two group leaders have unambiguously national and international reputations. The visibility of the other PIs in the unit appears more limited.

No information is provided on awards.

The participation as invited speakers to international conferences is good on cancer predisposition (mainly Li-Fraumeni syndrome) and splicing.

The unit has been very successful in raising funds from national research agencies (INCa, ANR, charities).

The participation to international networks is more limited. In particular there is no participation to Europefunded projects.

Most PhDs and post-docs of the unit come from the surrounding region meaning that the unit may have difficulties to recruit outside its neighborhood.

Socio-economic partnerships are excellent with the creation of three start ups.

The two group leaders are strongly involved in training activities  Appreciation on the management and life of the research unit Human genetics clearly constitutes the strong unifying link between both groups. All the technological developments are shared between the two groups. The unit has a very important structuring role for biomedical research in the hospital and reciprocally the hospital is clearly convinced that it must invest to support this unit.

The scientific life of the unit relies appropriately on weekly group meetings and lab meetings.

 Appreciation on the scientific strategy and the project

One can be very confident on the ability of the laboratory to generate new, important and useful results. The unit is facing very classical concerns to define its long term strategy. Indeed, almost by definition, genetic groups can hardly define a priori which genes will be revealed by their analyses and hence which assays will be required for functional follow-up analyses.

The neurogenetics group has clearly identified Drosophila as a model system to investigate the role of mutations. This appears to the committee as a sound option but to be really competitive, the Drosophila structure of the unit may need to be strengthened with additional staff. Some projects (oligogenic determinism of colorectal cancer) require being scaled up, in particular through collaborations, to reach the appropriate statistical power.

The analysis of splice variants, both in cancer predisposing genes and in neurogenetic disorders, is an important strength and an original aspect of the unit. The present step is to investigate the mutations using both the splice assay that has been developed and the analysis of appropriate tissues from patients. It is not fully clear what will be undertaken following this important, yet descriptive step.

In light of the number of projects of the unit, some projects, like immunotherapy and response to therapy, appear less competitive and hence should be revisited.

 Appreciation on the results

Overall the production of papers was quite good: they had 33 papers in international journals, with at least one member of the team as a first and/or last author. The Nature Genetics paper was a highlight and a breakthrough in the field of Alzheimer's disease (273 citations to date). The paper in Archives of General Psychiatry highlighted the genomic approaches to map genes involved in autism, schizophrenia, and mental retardation and will be significantly referenced for some time. However, the vast majority of the papers are coming from the team leader and more junior members of the team must be helped and encouraged to publish more.

The team has long-lasting, strong and stable interactions with neurologists of the hospital and this is a clear and highly productive advantage that differerentiates this team from others of similar focus and orientation.

 Appreciation on the impact, the attractiveness of the team and of the quality of its links with international, national and local partners

It is a well recognized lab, the team has a good reputation and they have a good ability to attract money from national institutions (in particular a large grants from the Plan Alzheimer, the foundation Alzheimer and the AFM and other grants from ANR, Gis maladies rares or fondation de France). They are strongly encouraged to seek funding from abroad, within EU and outside.

With respect to attractiveness of the team, clearly the current staff is barely adequate for the number and scope of ongoing projects and there seems to be little recruitment to the team from outside Normandie and Paris. Notable exceptions to this pattern are the recruitment of a foreign scientist and recently of a foreign post-doc to the group of Dr Lecourtois. Additional effort to increase attractiveness to students, post-docs and potential faculty outside the current recruiting vicinity must be made.

The publication of collaborative papers indicates good participation to international scientific networks and it is puzzling how this is not translated to European Union and International funding efforts.

A strong activity of the team is their ability to translate their research into organized databases and then to clinically useful tools (e.g. the minigene assay).

 Appreciation on the scientific strategy and the project Collectively, the scientific strategy is very well appreciated. The long-term projects are feasible, but a decision has to be made on whether the scale of the screening projects has to be increased or more extensive functional studies have to be implemented. For functional genetics it is clear that additional students/post-docs and even a new group will be necessary. This is exemplified by the Drosophila projects that will benefit greatly from increased personnel and even a new complementary analysis system, such as electrophysiology. With respect to the screening project, validation of their genetic results is necessary before moving to functional studies.

 Conclusion : -Summary

Overall, this is an internationally recognized group with promising future plans who will benefit greatly from being more extrovert with respect to international collaborations and successfully seeking EU or International funding. This will make an even greater impact of their work.

-Strengths and opportunities

Strengths are the close association with the hospital, excellent national recognition and impact. There are strong opportunities to develop functional assays for their clinical findings that lead to even better international networking and recognition.

-Weaknesses and threats

There are too many projects for too few people.

There is a question as to what follows after characterization of the sequence variants which affect splicing.

The formality and frame of their interaction with the bioinformatics group is not clear.

-Recommendations

They should increase the personnel or focus resources and efforts to the most promising projects. The project of biomarker of response to therapy was not presented. This is a highly competitive field and it is important for the team to assess whether the number of cases to be investigated will be appropriate to reach a sufficient statistical power.

Team : Cancer Genetics

Results of immunotherapy project based on CEA-based immunotherapy were recently published. They indicate that CEA may not be the appropriate target for immunotherapy. The new project that was presented was not fully convincing and need to be revisited.

An extreme originality is difficult to achieve in such a highly applied field -Impact:

The publications and other output are very good/good, taking into account the difficulty of publishing highestimpact manuscripts in the field of translational medicine (a total of 33 manuscripts with first or senior authorships from the group and 29 collaborative papers). Most publications are in good specialty journals (J Med Genet, Br J Cancer, Human Mutation) with a few in high-ranking journals such as J Clin Oncology or Gastroenterology.

-Partnerships:

Locally strong collaborations with clinical departments vital to work of laboratory.

The cancer genetics group collaborates with most cancer genetics French groups, in particular in the fields of breast and colon. Good national collaborations; strength of international collaborations less strong.

 Appreciation on the impact, the attractiveness of the team and of the quality of its links with international, national and local partners

The participation in international conferences is acceptable.

There are few international students or Post-Docs which probably reflects a common problem outside major cities in France in recruiting high-level scientists at all levels.

The national fund-raising is good, with multiple staff successful (large grants from the INCa on the "translational research" call, numerous other grants from Fondation de France, Ligue Nationale Contre le Cancer, Cancéropole Nord Ouest). International funding is however very limited.

The participation in national networks is very good; more limited international participation.

The team has produced several results very useful for clinical diagnostic practice; they have very good socioeconomic partnerships.

 Appreciation on the scientific strategy and the project Important and useful information will undoubtedly emerge from the proposed work, but there are concerns about several aspects of the proposed projects.

Several projects lack clear plan for the future, often manifest as a choice between large-scale screens (e.g. NGS) or strengthening functional studies. Some projects require greater ambition to build optimally on the sound basis that has been produced, e.g. a plan for following up the splice site changes either genetically or functionally.

The involvement of the full-time senior scientific staff will be critical in the success of individual projects, and these staff should be provided with the necessary resources to develop these. Some projects need consideration as to their scientific viability in the current location, e.g. oligogenomics without larger sample sizes and clearer medium-term plan, immunotherapy.

The biomarker project was not presented and it is not clear whether this remains an aim.

 Conclusion :

This project has been very successful in areas such as assessment of VUSs and characterization of Li-Fraumeni syndrome. The future plans should build on these successes and the patient cohorts accrued. However, plans should be specified more clearly, with more focus where appropriate (for example, making decisions between large-scale screens in humans and smaller-scale functional analyses in model systems where appropriate. We thank the review committee for the quality of the report and the constructive critical comments. Enclosed please find reply to questions, comments and additional information: p 4, p5 and p8 : Questions on the perspectives in bioinformatics : -Since the visit of the committee, we have learned that our project on NGS entitled " Creation of a Genomic Center for detection, interpretation of genetic variants and training to NGS data analysis" has not been selected in the context of the Grand-Emprunt Equipex call. Nevertheless, we got in december 2010 the plan B that we had prepared : we obtained, in the context of the plan Etat -Region, a funding of 320.000 euros and, from La Fondation pour la Recherche Medicale, 237.980 euros in the context of a national call. Furthermore, we obtained from the Fondation pour la Recherche Medicale a salary for an engineer in bioinformatics for 2 years.

-We have increased our weekly collaborations with the department of bioinformatics of the university of Rouen (Computer Science Laboratory -Data Processing in Biology and Health team LITIS-EA 4108, Prof Thierry Lecroq,; Dr. Helène Dauchel) which, through the MSc Bioinformatics, has trained many engineers in bioinformatics working in France, Europe, Canada, USA. In particular, this narrow interaction has recently allowed the development of the EVA (Exome Variation Analyzer) program which considerably facilitates the filtering and analysis of data generated by NGS, and we are in the process of finishing, thanks to the EVA program, the analysis of 12 exomes from patients with autosomal form of Alzheimer disease without PSEN or APP mutations. Sophie Coutant, engineer in bioinformatics is now working full-time in the unit. Furthermore, we also benefit from the expertise of the local company Interactive Biosoftware (http://www.interactive-biosoftware.com/) which had developed, in close collaboration with out unit, the Alamut TM software for mutation interpretation in medical molecular genetics, widely used by molecular genetics laboratories in Europe, North America and Asia. The combined expertise of the department of bioinformatics and the Interactive Biosoftware company creates an appropriate bioinformatics environment for the implementation and development of NGS planned before September 2011.

-A chaire d'excellence Inserm -University of Rouen has been obtained and will be opened in 2011 to recruit a PI in charge of NGS programs.

-p6 and p9: Appreciation on the quality of links with international partners : Although we have developed several scientific and technological international collaborations over the last four years, as demonstrated by the publications, it is right that we have not participated so far to Europe-funded projects. For the neurogenetics team, since the visit of the committee, we have learned that our project SMA-Var will be founded by the SMA European consortium. This will allow us to recruit a post-doc who has already been selected (Kathleen Mahias). For the cancer genetics team, considering the 2012 Health theme of FP7 (I. Biotechnology, generic tools and medical technologies for human health; I.2 Detection, diagnosis and monitoring with a specific focus on personalised medicine applications), we have decided to prepare and submit a project entitled "Classification of unclassified variants detected in inherited forms of cancers", which will be based on our expertise on splicing. Collaborators, who have been contacted and agreed, include Robert Hofstra (University of Groningen), Niels de Wind (Leiden University) and Lene Juel Rasmussen (University of Copenhagen).

p4 and p6 : Question on the anti-EGFR sensitivity and immunotherapy programs -We are aware that, like for all small to medium size research laboratories, a risk is the dispersion due to the number of projects and one of our permanent concern is to focus our projects on topics on which we have a national and international position. Considering our local position in a university hospital, we also think that we have the responsibility to stimulate the translational research for the benefits of patients. The important advance in the treatment of metastatic colorectal cancer, thanks to the anti-EGFR monoclonal antibodies, and the need to identify predictive markers of therapeutic response, led us in 2006 to create, within the genetics team, a group entiled "Biomarkers -Biotherapies of colorectal cancer" and based on the complementarity expertise between digestive oncology, pathology and molecular genetics. Just after the original work published in 2006 by the team of Pierre Laurent-Puig (Inserm U775 HEGP, Paris), we were the first group to show that KRAS mutation results into resistance to anti-EGFR. Our first paper on the topic (Di Fiore et al., Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by Cetuximab plus chemotherapy. British Journal of Cancer 2007) has now reached 257 citations and our published data were then confirmed by numerous publications which led to restrict the use of anti-EGFR to patients without KRAS mutations. Another article on the impact of TP53 mutations (Oden-Gangloff et al., British Journal of Cancer 2009) was highlighted in Nature Reviews Clinical Oncology 2009. Therefore, we think that our work initiated since 2006 enabled us to have a quick positioning on this subject at the international level and the medical repercussions of this work were consequent, our team having actively contributed to the development in France of KRAS genotyping.

-We have the wish to develop, in our fields of expertise, programs of therapeutic interest. In this context, we integrated in our unit an immunotherapy program under the direction of Jean-Baptiste Latouche who had developed, at the Memorial Sloan-Kettering Cancer Centre in New York, the artificial antigen presenting cells (AAPC) technology currently used in clinics within this Insititute. Our specific aim is to apply this technology to the RER colorectal cancers associated with the Lynch syndrome. After the implantation of this technology within our unit and the first application focused on CEA, this team has now finished to construct AAPC presenting the specific TGFRII frameshift epitopes associated with RER+ colorectal and the results recently obtained clearly demonstrate that it is possible to expand, thanks to these AAPC, specific cytotoxic T Lymphocytes from Lynch patients with germline MMR mutations.

-Therefore, we think that these programs are of potential interest and our laboratory might achieve in the future significant contributions in these fields. We also understand the constructive recommendation of the AERES committee to restrict our programs for the next years. Therefore, following the recommendations, we are going to explore both in the context of the local federative structure "the Institute for Biomedical Research and Innovation of



  Date and execution of the visit

-

  Opportunities Leadership role in the planned Institute for Research and Biomedical Innovation of Haute Normandie.



  Production results A1: Number of permanent researchers with teaching duties (recorded in N1) who are active in research 8 A2: Number of permanent researchers without teaching duties (recorded in N2) who are active in research 4 A3: Ratio of members who are active in research among staff members [(A1 + A2)/(N1 + N2)] 1 A4: Number of HDR granted during the past 4 years 6 A5: Number of PhD granted during the past 4 years 9 3  Specific comments  Appreciation on the results During the past 4-5 years the unit has contributed to important results.

  of researchers with teaching duties (Form 2.1 of the application file) 2.5 2 N2: Number of full time researchers from research organizations (Form 2.3 of the application file) of other researchers including postdoctoral fellows (Form 2.2 and 2.4 of the application file) 3 5 N4: Number of engineers, technicians and administrative staff with a tenured position (Form 2.5 of the application file) 1.5 1.5 N5: Number of engineers, technicians and administrative staff without a tenured position (Form 2.6 of the application file) 3.5 N6: Number of Ph.D. students (Form 2.7 of the application file) 3 N7: Number of staff members with a HDR or a similar grade 1.5 2



  of engineers, technicians and administrative staff without a tenured position (Form 2.6 of the application file) 3.5 N6: Number of Ph.D. students (Form 2.7 of the application file) 2 N7: Number of staff members with a HDR or a similar grade 3.5 4 Appreciation on the results -Relevance, Originality, Quality: Highly relevant translational research, especially in testing of variants of unknown significance (VUS) in breast and colon cancer families. Reference laboratory for Li-Fraumeni syndrome The quality of work in molecular diagnostics is high

Sciences du Vivant et Environnement

			Statistiques de notes globales par domaines scientifiques
					(État au 06/05/2011)
	Note globale	SVE1_LS1_LS2	SVE1_LS3	SVE1_LS4	SVE1_LS5	SVE1_LS6	SVE1_LS7	SVE2 _LS3 *	SVE2_LS8 *	SVE2_LS9 *	Total
	A+	7	3	1	4	7	6		2		30
	A	27	1	13	20	21	26	2	12	23	145
	B	6	1	6	2	8	23	3	3	6	58
	C	1					4				5
	Non noté	1									1
	Total	42	5	20	26	36	59	5	17	29	239
	A+	16,7%	60,0%	5,0%	15,4%	19,4%	10,2%		11,8%		12,6%
	A	64,3%	20,0%	65,0%	76,9%	58,3%	44,1%	40,0%	70,6%	79,3%	60,7%
	B	14,3%	20,0%	30,0%	7,7%	22,2%	39,0%	60,0%	17,6%	20,7%	24,3%
	C	2,4%					6,8%				2,1%
	Non noté	2,4%									0,4%
	Total	100,0%	100,0%	100,0%	100,0%	100,0%	100,0%	100,0%	100,0%	100,0%	100,0%
	*
	Intitulé UR / équipe	C1	C2	C3	C4	Note globale
	GÉNÉTIQUE DU CANCER ET DES MALADIES NEUROPSYCHIATRIQUES	A	A+	A+	A+	A+
	NEUROGÉNÉTIQUE [FREBOURG-CAMPION]	A+	A+	Non noté	A+	A+
	GÉNÉTIQUE DU CANCER [FREBOURG-FREBOURG]	A	A+	Non noté	A+	A+
	C1 Qualité scientifique et production
	C2 Rayonnement et attractivité, intégration dans l'environnement
	C3 Gouvernance et vie du laboratoire
	C4 Stratégie et projet scientifique

les résultats SVE2 ne sont pas définitifs au 06/05/2011. Intitulés des domaines scientifiques Sciences du Vivant et Environnement • SVE1 Biologie, santé SVE1_LS1 Biologie moléculaire, Biologie structurale, Biochimie SVE1_LS2 Génétique, Génomique, Bioinformatique, Biologie des systèmes SVE1_LS3 Biologie cellulaire, Biologie du développement animal SVE1_LS4 Physiologie, Physiopathologie, Endocrinologie SVE1_LS5 Neurosciences SVE1_LS6 Immunologie, Infectiologie SVE1_LS7 Recherche clinique, Santé publique • SVE2 Ecologie, environnement SVE2_LS8 Evolution, Ecologie, Biologie de l'environnement SVE2_LS9 Sciences et technologies du vivant, Biotechnologie SVE2_LS3 Biologie cellulaire, Biologie du développement végétal


president Michel Cosnard

Evaluation report

This report is the sole result of evaluation by the expert committee, the composition of which is specified below.

The assessments contained herein are the expression of an independent and collegial reviewing by the committee.

Unit name:

Host-Graft-Tumor Interactions -Cell and Gene Engineering

 Introduction

The unit is subdivided in two complementary teams. The team TIT (Tolérance et inflammation en transplantation) is headed by Mr Philippe SAAS and the team TIM-C (Thérapeutique Immuno Moléculaire des Cancers) is headed by Mr Christophe BORG. The TIT involves 7 subgroups: 1) "modulations des réponses immunes" -headed by Mr Sylvain PERRUCHE; 2) "immunomodulation et immunopathology" located in Dijon -headed by Mr Bernard BONNOTE-"labelled lipSTIC labex"; 3) "études cliniques en transfusions" headed by Mr Pierre TIBERGHIEN; 4) "transplantation inflammation lipoproteins et complications" headed by Mr Philippe SAAS and Mr Didier DUCLOUX, "labelled lipSTIC labex"; 5) "leucémies dérivées des pDC" headed by Ms Francine GARNACHE-OTTOU; 6) "cellules dendritiques et sous populations lymphocytaires en allogreffe de cellules hématopoïétiques"; 7) "maladie résiduelle et greffe d'ovaire" headed by Mr Christophe ROUX. The TIM C contains 3 subgroups which are 1) "activité signalisation des interactions hôte-greffon-tumeur", headed by Mr Christophe BORG; 2) "activité biologie moléculaire -thérapie cellulaire et génique", headed by Mr Christophe FERRAND and 3) "activité antigènes et réponses immunitaires", headed by Mr Olivier ADOTEVI. For the next contract, TIM-C will be joined by a new research group (EA3922) working on autophagy and cancer, which will reinforce the basic research side of the team.

History and geographical location of the unit

The "host-graft-tumor Interactions -cell and gene engineering" (UMR 1098) was created in 2001 at the Établissement Français du Sang (EFS-BFC) and was labelled UMR 1098 in 2012 by the INSERM. Research activities at the UMR 1098 are located in Besançon for 90% and in Dijon for 10%, the two universities being merged in the consortium COMUE UBFC (COMmunauté d'Universités et Établissements Université Bourgogne Franche-Comté). UMR 1098 is located in different buildings in the university, the Hospital campus or the EFS facilities. UMR 1098 was originally focused on allogeneic immune responses and their regulation (graft versus host disease (GVHD) after stem cell transplantation, or host versus graft reactions in solid organ transplantation), Graft Versus Leukemia effect (GVL) as well as reactions after transfusions. Later, host-tumor interactions became an important topic of the unit that can be perceived in the concept of "mirror image" (unsuitable mechanisms involved in one direction might be exploited in the other one). In parallel, mechanisms of immune mediated inflammatory diseases (IMID) also became a transverse thematic. Importantly, all subjects are related to the clinical practice of the Centre Hospitalier Régional Universitaire CHRU, and most of them are the continuation of previous research. The UMR 1098 unit has evolved from adoptive allogeneic immunotherapy to immune cell-based therapies based on advanced therapy medicinal products (ATMP), including allogeneic NK cells, apoptotic leukocytes, monocyte-derived suppressive cells and skin substitutes (the skin engineering platform). A large biomonitoring platform dedicated to biotherapies and innovative technologies (directly connected to a biological resource center and a clinical investigation center) has been created including up to 28 sample collections and biological follow-up of patients from more than 54 clinical trials. So far, there are more than 15,000 samples collected. The unit obtained the ISO 9001 certificate in 2008 that was renewed in 2015.

Management team

Mr Philippe SAAS is the head of the unit.

HCERES nomenclature

SVE1_LS6, SVE2_LS8

Scientific domains

TIT and TIM-C scientific subjects are related to inflammation and immunity, in the contexts of transplantation, cancer, hematopoietic stem cell transplantation and red cell transfusion. 2  Overall assessment of the unit

Unit workforce

Unit workforce

Introduction

The unit is dedicated to the understanding of immunological mechanisms, inflammation and immunity in different clinical contexts involving immune system with a typical translational approach. These contexts include allogeneic immune responses in renal transplantation or hematopoietic stem cell transplantation, blood transfusions, auto-immunity and malignancies. Identification of biomarkers of disease evolution and follow-up of treatment responses has become an important goal of the unit. Another major objective is the development of innovative therapeutic strategies by using new Advanced Therapy Medicinal Products (ATMP) produced by the different internal teams in the unit, in a GMP (Good Manufacturing Practice)/GCP (Good clinical practice) manner (apoptotic cells, SuperMApo, HuMoSC, UCPVax, Mecaskin). Clinical trials and patient cohorts have significantly progressed compared with the 2011 evaluation. Consequently, major grants and patents have been obtained by the unit.

Global assessment of the unit

The unit has performed excellent translational research, with a high number of publications in very good international journals and an important number of theses defended. Notable developments regarding new biotherapies including ATMP or cell therapy as well as innovative biomarkers have been obtained. The management and team atmospheres are excellent as attested during the discussions with all team members (scientists, technicians and students). The integration in the university campus and the hospital (FHU) is remarkable and strengthens the future existence of the unit. The next five-year plan is convincing, with pertinent questions regarding the FHU/CIC context and unit expertise. In this excellent context, the committee might regret the incapability to recruit young researchers or post-docs. An increased number of full time scientists, completely dedicated to basic research, by allowing publishing in very high impact factor journals, might also enhance scientific excellence and attractivity for post-docs.

Strengths and opportunities in the context

There is a compelling and remarkable promotion of translational research with constant concern to evolve from basic science to clinical trials (e.g. cell-based therapy studies) and with a great involvement of physicians. The questions that are addressed are topical and highly relevant for both basic and translational research. The established patient cohorts and clinical studies supported by a BioMonitoring platform are impressive. The ISO 9001 certification (2008 certification attesting for an established quality management process) is a useful tool for constant quality improvement.

The small shift in the research strategy is also well motivated by the increase in the team size and in the expertise of the team members, including the clinicians. The unit expertise is also highlighted by the strong immunomonitoring platform and the good technical support.

The strong support of the university, the hospital and EFS, as well as the involvement of the University of Franche-Comté COMUE development and education/training initiative are obvious strengths. The management of two M2 master degrees (M2), dealing with Host-graft and host-tumor interactions, or Molecular and cellular signalization, both headed by a senior scientist of the unit are the basis for the recruitment of master students and further PhD students.

Several national and international collaborations have been set up, grants from public institution (with a high capacity to obtain competitive grants such as PHRC, INCA) and industrial partners have been obtained.

Weaknesses and threats in the context

The research staff is limited in the number of full-time scientists. Most of the scientists are either permanent professors that can only dedicate part of their time to research, or Medicine Professors with heavy teaching and clinical duties. The lack of attractivity probably results in the small number of post-docs and still remains a real issue.

The spread of projects with sometimes only little interactions between internal teams and the competitive characteristics of some thematics (i.e. T CAR…) compared to the relatively small size of the team might be an issue. Although most of the projects show a significant originality and a very strong clinical perspective, the clinical translation may benefit from a more thorough mechanistic analysis.

The cost of development and the difficulty of obtaining the authorization of Advanced Therapy Medicinal Product (ATMP), as well as the European competitive aspects are clear threats.

In addition, the scattering of offices and lab facilities has been considered as a weakness by the committee.

Recommendations

Most of the senior researchers have heavy teaching duties and/or hospital duties and the mentoring of students should be reconsidered. Indeed, due to these duties, they have reduced time for supervision of master and PhD students. The main challenge is now to increase the number of full-time senior researchers and post-docs in order to maintain the quality of the research, to stabilize the teams and to keep focus on the unit's strengths.

In some approaches, a more thorough mechanistic analysis might strengthen the fundamental aspects of the research and might improve the impact factors of publications.

Because of the complexity/multiplicity of subjects that will be developed in the next 5 years in team 1 equivalent, the committee recommends that the new foreseen director be mentored by the former director.

International visibility of team 2 could further increase by favouring submissions to high rank/profile journals in a more systematic way, and also by participating to European networks in addition to the very good ATMP activity. Focusing on a reduced number of projects could improve the impact of Team 2 publications in the future. They should continue their efforts to try to patent their findings, as this is a source of industrial collaborations and grant money as they have experienced in the past. We also recommend to gather the teams in the same location to reinforce their interactions; this is planned and should be realized in the near future.

Qualified research supervisors (HDR) or similar positions 26

		Number on	Number on
		30/06/2015	01/01/2017
	N1: Permanent professors and similar positions	31 (9.5FTE)	40 (13.6FTE)
	N2: Permanent researchers from Institutions and similar positions	3	3
	N3: Other permanent staff (technicians and administrative personnel)	20 (18.1FTE) 21 (19.1FTE)
	N4: Other professors (Emeritus Professor, on-contract Professor, etc.)
	N5: Other researchers from Institutions (Emeritus Research Director, Postdoctoral students, visitors, etc.)	8 (2.6FTE)
	N6: Other contractual staff (technicians and administrative personnel)	6 (5.1FTE)
	N7: PhD students	28
	TOTAL N1 to N7	96 (66.3FTE)
	Unit record	From 01/01/2010 to 30/06/2015
	PhD theses defended	28
	Postdoctoral scientists having spent at least 12 months in the unit	3
	Number of Research Supervisor Qualifications (HDR) obtained during the period	4


M Olivier Lantz

Nathalie Mrs

Chaput

M Philippe Grimbert

M Peter Staeheli

M Michael Schindler

Annette Mrs

Larsen

Ana-Maria Mrs

Lennon

M Christian Drouet

Efs Mrs

CSS Catherine Labbe Jullie

The visit took place on November, 5, 2010 from 9 AM to 4 30 PM. After a closed door meeting with the committee members, the former head of the unit presented the main past results. The general strategy of the unit was then described by the new head of the unit. The 2 different group leaders presented their past, present and future projects. A poster session followed. The committee then met with the ITA, students and staff scientists before outlining the main conclusions during a closed door meeting.

 History and geographical localization of the research unit, and brief presentation of its field and scientific activities:

The unit is the only one in Besançon to be affiliated to INSERM. It is also affiliated to EFS and the University of Franche-Comté. It is located in several buildings (University, hospital and EFS) and uses many EFS and IFR facilities. Most of the permanent researchers have teaching and hospital duties. During the last period, the unit was headed by P TIBERGHIEN and encompassed two research groups : one group studies the mechanisms of and the way to modulate host-graft interaction and the second one studies the rejections of cancers and grafts by the immune system and the way to modulate this process. The first group will be headed by P. SAAS who will be also the head of the unit while the second group will be headed by C. BORG.

 Management team:

Philippe SAAS and Christophe BORG are group leaders.

 Staff members (on the basis of the application file submitted to the AERES): 2  Overall appreciation on the research unit  Summary:

The unit is mainly dedicated to translational research. The publication record is good with abundant production including several papers in the best journals of the categories proposed by the Journal of Citation Reports including: "transplantation", "urology and nephrology" or "hematology" (Blood, JASN, Am J Transplantation, Kidney int.) during the last 4 years. The unit has a long standing expertise in cellular therapy with particularly the use of genetically modified effector lymphocyte that was the basis of interesting new results. The interactions between the monitoring unit and the kidney transplant group are highly productive. The expertise of the unit with regards to transplantation epidemiology and teaching is quite unique in France. There is a good integration between the human and the mouse models. The unit was quite attractive as judged by the hiring of new staff scientists, which, however, should not lead to more spreading of the efforts. Indeed, the projects are already quite numerous and more focus would probably be necessary to improve the impact of the published papers.

The students are well mentored and the technical staff is well managed. The technical resources, both internal and external, look appropriate to carry out the proposed work.

 Strenghts and opportunities:

Important translational research activity with a nice integration with the 2 Clinical Investigation Centers (CIC): one dedicated to biotherapy and the other to innovative technologies. Good scientific production, good student mentoring. Good working settings.

 Weaknesses and threats:

Most of the senior researchers have heavy teaching and hospital work load and there is some lack of focus in the unit.

The clinical translation may benefit from a more thorough mechanistic analysis, and would, in some specific cases, also benefit from collaboration with colleagues with expertise in drug development.

 Recommendations to the head of the research unit:

Many projects are centered on the specific expertises of the unit and should be continued. Because most of the members of the unit are quite experienced with mixed teaching/hospital appointments the numbers of projects in each team is high. The arrival of new researchers should not lead to an increase of the number of projects but should be the opportunity to acquire the expertise lacking in the unit to allow better mechanistic studies. For the next renewal, the new director of the unit should consider splitting the 2 current big teams into several more focused groups. This would allow a better structuring of the unit and projects. The number of students in the skin engineering platform is rather high for very technical and applied projects. The unit is dedicated to translational research with a focus on cellular therapy for malignant diseases or transplantation. The expertise of the unit is original in France. The integration between the different themes seems to be adequate and the different components of the unit are complementary.

The skin engineering platform seems to be productive with regards to the patents applied for.

 Appreciation on the impact, the attractiveness of the research unit and of the quality of its links with international, national and local partners:

New permanent researchers who have been trained in excellent foreign laboratories have been recruited.

Numerous grants have been obtained from public and private sources. There are several collaborations with the industries. Several collaborations are ongoing at the European level. Several patents have been applied for.

 Appreciation on the strategy, management and life of the research unit:

The whole unit meets weekly and there are also specific weekly meetings for each team and subgroup. The laboratory council meets every two months. The unit seems to be quite well managed and all the actors seem to be satisfied with the current situation. However, several of the laboratory members who are the most involved in research seem to be principal investigator and lead independent projects. The official recognition of this configuration would enable to better evaluate the necessity, or not, of focusing some groups.

Most of the researchers are heavily involved in teaching with participation in several Master programs at the regional and national level including the management of masters or other teaching modules.

 Appreciation on the project:

The specific assessment of the projects will be evaluated for each team.  Staff members:

According to the provided document, the delineation between the two teams was not completely clear. In addition, members of the platforms were not clearly included in one or the other of the two teams (TIT or TIMC) and thus could not be evaluated.  Appreciation on the results:

The team 1 (TIT) project is divided into 3 themes:

-Modulation of allo-immunity by IV injection of apoptotic bodies: this topic has been studied for over 10 years and the team has a clear expertise and external visibility on this topic, mainly related to results obtained with in vitro and experimental data.The transfer to humans appears to be very laborious. The current lack of clinical transfer seems to be related to the improvement of the clinical outcome leading to an absence of indication of the procedure.

-Effectors involved in GVHD: important topic and important notoriety of the team in this area. A new direction is being developed on the role of pDCs in the induction of Treg and/or Th17. The project developed on leukaemic pDCs is interesting but is rather divergent from the other topics of the team. However, the cohort of patients is unique.

Collaboration with groups specialized in related topics could be considered: other leuckemia of innate cells, biology of pDCs for instance.

-Study of the immune reconstitution after organ transplantation : Recovery of immune system post allograft is a very original topic in France. P SAAS Team has acquired a good notoriety in this field. This topic is mainly developed through translational studies performed on cohorts of renal transplant.

Numerous publications of good quality. However, the number of subjects that are studied likely reduces the ability to publish in high impact journals.

Many national and international collaborations.

 Appreciation on the impact, the attractiveness of the team and of the quality of its links with international, national and local partners:

This team is attractive because it provides a strong immuno-monitoring platform and good technical support with a large number of technical staff. There is a strong support from the EFS. Several national and international collaborations have been set up. There is a good integration between the university, the hospital and EFS.

Although it appears to be difficult to attract post-doc to Besançon, the team has been able to recruit two senior researchers.

Several grants from public institution and industrial partners.

 Appreciation on the strategy, management and life of the team:

Very good contribution and independence of young researchers who independently manage their research and apply for funding. Management is good with well-supervised technicians, regular meetings (weekly bibliographical meetings and data presentation + subgroup meetings). Technical and administrative staff, students and young researchers seemed very satisfied.

Some cutting edge projects, however the proliferation of subjects could lower the level of publication on each topic.

All the researchers have a dual university/hospital appointment. Therefore all the scientists have important teaching involvement including the organisation of masters or other teaching modules.

 Conclusion :

Good projects, good scientific production. The focus is translational research and the patient is at the center of the projects even in preclinical ones. An outstanding quality assurance system for a research team due to a strong link with EFS.

Too few full time researchers, too many "small" projects (microvesicles, pDC leukaemia).

The organisation of the group was not clear as the name of the PI for each subject was not clearly provided in the written document (except to some extent in appendix #3). The number of projects for each scientist (especially for those who have teaching and hospital duty) looks too high. Perhaps P SAAS should focus on fewer subjects to be able to publish in journals with higher IF in the future. For the next renewal, the team could be split into several more focused groups. This would allow a better structuring of the team and projects. The projects are original with potential clinical application. However the will to rapidly transfer molecules into the clinic may prevent the analysis of the exact molecular mechanisms involved (particularly STAT3 and CX3CL1 topics) and this may be counter-productive. This has the further effect of decreasing the impact of publications. Two clinical trials using NK cell transfer combined with mabs are innovative and very original in France.

Numerous publications of good quality. However, the number of topics studied likely reduces the ability to publish in high impact journals.

Many national and international collaborations. Many partnerships with industrials (antisoma biotech, invectys biotech, teracetys, Cytheris)

 Appreciation on the strategy, management and life of the team:

This team is attractive because it provides a strong immuno-monitoring platform and good technical support with a large number of technical staff. There is a strong support from the EFS. Several national and international collaborations have been set up. There is a good integration between the university, the hospital and EFS.

Although it appears to be difficult to attract post-doc to Besançon, the team has been able to recruit one senior researcher.

Several grants from public institution and industrial partners.

Very good contribution and independence of young researchers who independently manage their research and apply for funding. Management is good with well-supervised technicians, regular meetings (weekly bibliographical meetings and data presentation + subgroups meetings). Technical and administrative staff, students and young researchers seemed very satisfied.

Some cutting edge projects (link between p-STAT3 and MICA expression, CX3CL1 topic). However the lack of a precise description of molecular mechanisms involved could lower the level of publication on each topic.

Contribution of the team members to teaching and to the structuring of the research at the local level.

All but two of the researchers have a dual university/hospital appointment. Therefore all the scientists have important teaching involvement with the organisation of masters.

 Conclusion :

Innovative and relevant projects with interesting scientific results and publications. However the molecular mechanisms are not sufficiently explored.

Several cellular clinical trials (2 NK cells transfer along with monoclonal mabs and one adaptive transfer of allogeneic suicide gene modified lymphocytes. C. BORG has a strong expertise in the NK cell field (numerous publications) and P. TIBERGHIEN and C. FERRAND have a strong expertise in allogeneic suicide gene modified lymphocytes with a long experience and numerous publications.

For adoptive transfer of NK cells in patients with colorectal cancer, it seems that inclusion criteria are obsolete. Indeed there is no determination of the mutational status of KRAS and patients with mutated KRAS should not be included in this clinical trial according to international recommendations. An amendment should be proposed. However it should be noted that this team is the only one in France to offer this type of cell therapy treatment. Also, the team has to be praised for this type of initiative as the implementation of this type of approach is very complicated and laborious (financial difficulties, organizational difficulties, cellular production and regulatory difficulties).

Great industrial partnerships, very dynamic translational research program.

Lack of full time researchers but recent recruitment of a young PI.

The young researchers should have been invited to present during the visit since they independently supervise their research and apply for funding.

INTERACTIONS HÔTE-GREFFON-TUMEUR ET INGÉNIERIE CELLULAIRE ET TISSULAIRE

Answer to the report from AERES visiting committee concerning the research unit UMR645: Host-Graft Interactions -Cell and Gene Engineering

We have read in depth the report of the visiting committee. We thank the visiting committee for this report. We were delighted to learn that the committee appreciated: i) the "important translational research activity with a nice integration with 2 clinical Investigation centers (CIC): one dedicated to biotherapy and the other to innovative technologies", ii) our good scientific production ("The publication record is good with abundant production including several papers in the best journal of the categories proposed by the Journal of Citation Reports: "transplantation", "urology & nephrology" or "hematology" [Blood, JASN, Am J Transplantation, Kidney int. "]…) and iii) our "good student mentoring" and "good working settings". We were also pleased to learn that TEAM 1 (Tolérance et Inflammation en Transplantation) has a "good/important notoriety" or "external visibility" in the field of "modulation of allo-immunity by IV apoptotic bodies", "Effectors involved in GvHD" and "immune reconstitution after organ transplantation" and that TEAM 2 (Thérapeutique ImmunoMoléculaire des Cancers) is "the only one in France to offer this type of" NK "cell therapy treatment".

We would like to comment the following remarks of the committee's report.

We fully agree that "most of the permanent researchers have heavy teaching duties". However, as mentioned in page 2 of the report, "the expertise of the unit with regards to transplantation epidemiology and teaching is quite unique in France" or in page 5 "Most of the researchers are heavily involved in teaching with participation in several Master programs at the regional and national level including the management of masters or other teaching modules". Indeed, two members of the unit manage two different M2 master degrees: one dedicated to cell therapy (M2 Ingénierie Cellulaire et Tissulaire) and the other one to transplantation (M2 relation Hôte-Greffon).

Concerning the Staff members and the organizational chart, the report mentions that "… the delineation between the two teams was not completely clear. Members of the platforms were not clearly included in one of the two teams…" as well as "…members of both transfer structures are not clearly included in any one of the two teams...". In order to clarify the "who do what" chart, we would like to highlight the following: our research unit includes two research teams ("Tolérance et Inflammation en Transplantation" and "Thérapeutique ImmunoMoléculaire des Cancers") strongly supported by 6 biotechnological platforms as mentioned in the report (please see page 7 and page 8, "... a strong immuno-monitoring platform and good technical support"). These 6 platforms are the following: the animal facility, the cell therapy translational research unit, a monoclonal antibody production unit (in collaboration with Diaclone), a skin translational research unit and 2 clinical investigation centers including a immunomonitoring platform involved in patient biological followup. These platforms are tightly incorporated in both teams and under the management of unit members. In addition, these platforms include technicians and engineers working under the supervision of the platform manager but who are not included in the organizational chart of the two teams.

We apology for not clearly indicating the name of the respective principal investigators (PI) in the written document as stated in the report page 7: "…the name of the PI for each subject was not clearly provided in the written document except to some extend in the appendix #3". However, we provided the name of the PI respectively to their projects during the meeting with the visiting committee. Committee members had time to meet and interact with each of them during the poster session. We would like to provide you with the It was mentioned in the report that the research unit develops too many projects (please see page 4: "the projects are already quite numerous and more focus would probably be necessary…"; "…there is some lack of focus in the unit…"; "…the numbers of projects in each team is high…"). However, as mentioned in the report, most of the projects lead to publications (please see page 6: "Numerous publications of good quality. However, the number of subjects that are studied likely reduces the ability to publish in high impact journals.") and these projects are of interest for patient health. Indeed, as mentioned in the report, our research unit is focused on "translational research" and "the Patients is at the center of the projects even in preclinical ones.". Nevertheless, we will take into account the advice to "focus on fewer subjects to be able to publish in journals with higher IF in the future. For the next renewal, the team could be split into several more focused groups. This would allow a better structuring of the team and projects."

In the project proposed by our research unit, a project developed on leukemic pDC was considered as "too small" or "interesting but is rather divergent from the other topics of the team". However, as mentioned "the cohort of patients is unique". Indeed, a large number (n=46) of leukemic pDC samples have been collected from all over France and collaborations with experts in the field of hematological malignancies or transcriptomic and genomic analysis (including E MacIntyre or C UMR645 -Etablissement Français du Sang de Bourgogne Tel : +33 (0)3.81.615.615

Preudhomme) have been set up. ontogeny. Furthermore, the study of pDC in the setting of transplantation is common to other 1 projects.

Concerning the modulation of allo report mentions that "The transfer to humans appears to be very laborious team have a clear expertise and bench to the clinical setting is due to safety our group. Before a translation to allogen that ciclosporin A interferes with the beneficial effects of IV apoptotic cell infusion (Bonnefoy et al., Leukemia, 2008). Ciclosporin A is used in routine alone or in association with mycophenolate mofetil in almost all patients receiving allogeneic hematopoietic cell transplantati approach may be ineffective in t infusion at the time of allogeneic hematopoietic cell transplantation is to avoid ciclosporin A and deplete donor T cells from the graft. under preparation.

Then, concerning our adoptive transfer of NK cells in patients with colorectal cancer study), the experts stated that "inclusion criteria are obsolete. Indeed there is no determination of the mutational status of KRAS and patients with mutated KRAS should not be included in this clinical trial according to international recommendations. An amendment should be proposed be stated that in our setting, the antibody directed against EGF signaling pathway but is used -d transfer-to both target cells expressing EGF infused NK cells. These NK cells are infuse Moreover, some industrial mon dependent cytotoxicity are unde #2010-022983-11) were recently Lastly, we also regret that "the young researchers visit since they independently supervise their research and apply respect, we followed strictly the request of the AERES committee leaders had to present the project Preudhomme) have been set up. This leukemic pDC is a valuable model to understand human pD Furthermore, the study of pDC in the setting of transplantation is common to other rning the modulation of allo-immune response by intravenous infusion of apoptotic cells, The transfer to humans appears to be very laborious" despite the fact that " clear expertise and external visibility on this topic". This delay in the transfer is due to safety and to efficacy considerations and to data obtained in a translation to allogeneic hematopoietic cell transplantation setting, we showed es with the beneficial effects of IV apoptotic cell infusion (Bonnefoy et al., Ciclosporin A is used in routine alone or in association with mycophenolate mofetil patients receiving allogeneic hematopoietic cell transplantation. Thus, our cell therapy this setting. An alternative approach to use intravenous apoptotic cell of allogeneic hematopoietic cell transplantation is to avoid ciclosporin A and deplete donor T cells from the graft. We are currently pursuing in this direction adoptive transfer of NK cells in patients with colorectal cancer inclusion criteria are obsolete. Indeed there is no determination of the ational status of KRAS and patients with mutated KRAS should not be included in this clinical trial according to international recommendations. An amendment should be proposed he antibody directed against EGF-R is not used to target the EGF during a short period of time along with allogeneic target cells expressing EGF-R in the hepatic tumors and to trigger cytotoxicity These NK cells are infused in the hepatic artery, in the vicinity of the metastasis noclonal antibodies (such as RO5083945) opti er development. Phase I/II clinical trials (NCT007 y approved with similar inclusion criteria and are the young researchers" have not been "…invited to present during the visit since they independently supervise their research and apply for funding the request of the AERES committee prior to the to present the projects of the unit.

Yours sincerely

Prof. Philippe SAAS 3 1 Bd A Fleming BP1937 philippe.saas@efs.sante.fr leukemic pDC is a valuable model to understand human pDC Furthermore, the study of pDC in the setting of transplantation is common to other TEAM immune response by intravenous infusion of apoptotic cells, the " despite the fact that "the This delay in the transfer from the considerations and to data obtained in ic hematopoietic cell transplantation setting, we showed es with the beneficial effects of IV apoptotic cell infusion (Bonnefoy et al., Ciclosporin A is used in routine alone or in association with mycophenolate mofetil on. Thus, our cell therapy . An alternative approach to use intravenous apoptotic cell of allogeneic hematopoietic cell transplantation is to avoid ciclosporin A and n and a clinical trial is adoptive transfer of NK cells in patients with colorectal cancer (NK-EGFR01 inclusion criteria are obsolete. Indeed there is no determination of the ational status of KRAS and patients with mutated KRAS should not be included in this clinical trial according to international recommendations. An amendment should be proposed.". However, it must R is not used to target the EGF-R allogeneic NK cell adoptive R in the hepatic tumors and to trigger cytotoxicity of the vicinity of the metastasis. imized for antibody-721266 and EUDRACT ongoing.

invited to present during the for funding". However, in this e visit that only team

Prof. Philippe SAAS



  Date and execution of the visit:

3

   Specific comments  Appreciation on the results:

4

  Appreciation team by team  Title of the team and name of the team or project leader :  HOST-GRAFT INTERACTIONS : Philippe SAAS TEAM 1: Tolerance et inflammation en transplantation (TIT)

 8 

 8 Title of the team and name of the team or project leader :  HOST-TUMOR INTERACTIONS : Christophe BORG TEAM 1: Thérapeutique immuno moléculaire des cancers (TIMC)  Staff members: There are many academic members not included in the organizational team entitled TIT (P SAAS) or the team entitled TIMC (C. Borg) (cf. Appendix 2). In addition, members of both transfer structures are not clearly included in any one of the two teams (TIT or TIMC). Past Future N1: Number of researchers with teaching duties (Form 2.1 of the application file) 4 7 N2: Number of full time researchers from research organizations (Form 2.3 of the application file) of other researchers including postdoctoral fellows (Form 2.2 and 2.4 of the application file) 2 3 N4: Number of engineers, technicians and administrative staff with a tenured position (Form 2.5 of the application file) 5 5 N5: Number of engineers, technicians and administrative staff without a tenured position (Form 2.6 of the application file) N/A N/A N6: Number of Ph.D. students (Form 2.7 of the application file) 3 8 N7: Number of staff members with a HDR or a similar grade 5 Appreciation on the results: The project team 2 (TIMC) is divided into 2 themes: -Signaling pathways that modulate host-tumor-graft interactions (STAT3 and CX3XL1/CX3CR1) -Development and validation of innovative immunological therapeutics (deltaCD20, NK cells transfer, tumor antigens vaccination)

Sciences du Vivant et Environnement

				Statistiques de notes globales par domaines scientifiques
						(État au 06/05/2011)
		Note globale	SVE1_LS1_LS2	SVE1_LS3	SVE1_LS4	SVE1_LS5	SVE1_LS6	SVE1_LS7	SVE2 _LS3 *	SVE2_LS8 *	SVE2_LS9 *	Total
		A+	7	3	1	4	7	6		2		30
		A	27	1	13	20	21	26	2	12	23	145
		B	6	1	6	2	8	23	3	3	6	58
		C	1					4				5
		Non noté	1									1
		Total	42	5	20	26	36	59	5	17	29	239
		A+	16,7%	60,0%	5,0%	15,4%	19,4%	10,2%		11,8%		12,6%
		A	64,3%	20,0%	65,0%	76,9%	58,3%	44,1%	40,0%	70,6%	79,3%	60,7%
		B	14,3%	20,0%	30,0%	7,7%	22,2%	39,0%	60,0%	17,6%	20,7%	24,3%
		C	2,4%					6,8%				2,1%
		Non noté	2,4%									0,4%
		Total	100,0%	100,0%	100,0%	100,0%	100,0%	100,0%	100,0%	100,0%	100,0%	100,0%
	*
				A	A	A+	A	A
	IMMUNOMOLECULAR THERAPIES IN CANCER [SAAS-BORG]	A	A	Non noté	A	A
		TOLERANCE AND INFLAMMATION IN TRANSPLANTATION [SAAS-SAAS]	A	A+	Non noté	A	A
	C1	Qualité scientifique et production
	C2	Rayonnement et attractivité, intégration dans l'environnement
	C3	Gouvernance et vie du laboratoire
	C4	Stratégie et projet scientifique

les résultats SVE2 ne sont pas définitifs au 06/05/2011. Intitulés des domaines scientifiques Sciences du Vivant et Environnement • SVE1 Biologie, santé SVE1_LS1 Biologie moléculaire, Biologie structurale, Biochimie SVE1_LS2 Génétique, Génomique, Bioinformatique, Biologie des systèmes SVE1_LS3 Biologie cellulaire, Biologie du développement animal SVE1_LS4 Physiologie, Physiopathologie, Endocrinologie SVE1_LS5 Neurosciences SVE1_LS6 Immunologie, Infectiologie SVE1_LS7 Recherche clinique, Santé publique • SVE2 Ecologie, environnement SVE2_LS8 Evolution, Ecologie, Biologie de l'environnement SVE2_LS9 Sciences et technologies du vivant, Biotechnologie SVE2_LS3 Biologie cellulaire, Biologie du développement végétal

UMR645 -Etablissement Français du Sang de Bourgogne Franche-Comté -1 Bd A Fleming BP1937 25020 Besançon CEDEX -France Tel : +33 (0)3.81.615.615 -Fax : +33 (0)3.81.615.800 -E-Mail : philippe.saas@efs.sante.

fr Unité Mixte de Recherche U 645 Interaction hôte-greffon et ingénierie cellulaire

	Besançon, March 14 th , 2011
	Prof. Philippe Saas, PhD
	UMR645 Inserm / EFS BFC / Université de Franche-Comté
	1 Boulevard A Fleming, BP1937
	25020 Besançon Cedex

  table below indicating the name of each PI and their research theme.

	TEAM 1:
	S Perruche	Modulation of allo-immunity by IV injection of apoptotic bodies
	B Gaugler	Effectors (APC, lymphocytes) involved in GVHD
	D Ducloux	Immune reconstitution and organ transplantation-related complications
	TEAM 2:
	C Borg	Investigating the signaling pathways that modulate host-tumor-graft
		interactions
	C Ferrand / O Adotevi	Development and validation of innovative immunological therapeutic
		strategies