The CALYM CARNOT. INSTITUT in Advancing LYMPHOMA Diagnosis & Treatment TOGETHER THE CALYM CARNOT

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1 The CALYM CARNOT INSTITUTE in 2016 Advancing LYMPHOMA Diagnosis & Treatment TOGETHER 1 INSTITUT in 2016 EN

2 CONTENT 2016 One of CALYM s major challenges over time is to foster the preclinical/clinical research continuum with regard to lymphoma therapies and diagnosis. A major new step was reached in 2016 in the development of our institute, with the Carnot 3 institute accreditation awarded by the French Government, ensuring its sustainability. This accreditation was accompanied by a change in the scope of CALYM with the integration of new teams internationally recognized for the quality of their research and we are delighted. This year was very rich in science with a strong participation of our researchers in international scientific congresses and the publication of preclinical and clinical research results in high-impact journals, particularly on mantle cell lymphoma. The development of our partnering R&D was boosted by the deployment of the FINDMED consortium, which, like GLOBAL CARE, is expected to create new partnerships with French SMEs. The organization of FAID 2016 by GLOBAL CARE was a real success which increased our visibility in the United States and allowed to present France as a strategic step for clinical developments. Another highlight of 2016 was the organization of our third scientific and partnering day in October, which allowed us to meet nearly 40 industry representatives and strengthen ties with our partners but also between the teams of the consortium also corresponded to the renewal of our ISO 9001:2008 quality certification for the management and monitoring of our research activities and the coordination of our lymphoma viable cells CeVi_ collection, a guarantee of our professionalism. This renewal should pave the way for our next big step, next year, which is the transition to the new ISO 9001:2015 standard. CALYM s perspectives are ambitious, with personalized medicine being a major focus of its development strategy. All the conditions are now met within our consortium to carry out our mission to serve patients and continue to advance lymphoma research together! Gilles Salles CALYM Chairman I. CARNOT 3 ACCREDITATION: A NEW STEP FOR CALYM P. 4 II. HIGH SCIENTIFIC PRODUCTION AND ACTIVITY P. 6 Strong commitment to scientific congresses A unique training offer Scientific focus Clinical research Diverse scientific resourcing projects CeVi_Collection collaborative project III. DEVELOPMENT OF PARTNERSHIPS P. 15 Partnering research key figures Strong relationships with other Carnot and the network Highlight: CALYM s third scientific and partnering day International development Two examples of success stories with industry 2 INSTITUT in 2016 INSTITUT in

3 I. CARNOT 3 ACCREDITATION A NEW STEP FOR CALYM List of public research laboratories members of CALYM TEAM NAME LABORATORY TEAM LEADER Anticancer antibodies UMR1052 Inserm 5286 CNRS Centre Léon Bérard, Cancer Research Center of Lyon C. Dumontet Control of the B cell immune response and lymphoproliferations UMR7276 CNRS, Biology and Healthcare Research Center M. Cogné J. Feuillard Immunity and cancer U1068 Inserm UMR7258 CNRS, Centre de Recherche en Cancérologie de Marseille B. Olive Immunology & oncogenesis of lymphoid tumor U955 Inserm, Mondor Institute of Biomedical Research P. Gaulard On 6 July 2016, CALYM received Carnot 3 institute accreditation by the French Ministry of Research and Higher Education in its new scope: the LYSA and LYSARC associations and thirteen leading public research laboratories* in the lymphoma field. Genomic instability and human hemopathies Clinical and experimental models of lymphomagenesis Laboratory of molecular mechanisms of hematologic disorders and therapeutic implications U1104 Inserm UMR7280 CNRS, Centre d'immunologie de Marseille-Luminy UMR1052 Inserm 5286 CNRS Centre Léon Bérard, Cancer Research Center of Lyon U1163 Inserm 8254 CNRS ERL, Imagine Institute for Genetic Diseases B. Nadel G. Salles L. Genestier O. Hermine With the renewal of the certification, CALYM is one of the twenty-nine French research institutes to be granted accreditation, out of forty-five applications received by the Ministry. They will benefit from the contribution of their partnering research revenues through the National Research Agency, up to a stable budgetary amount of 57 M in This accreditation is now sustainable, each Carnot institute being evaluated every three years, when the scope of the consortium might be subject to change. This is a new important step for the institute, which will have a significant impact towards making progress in lymphoma research. states Pascal Deschaseaux, CEO of CALYM. One of CALYM s major challenges over the period is to foster the preclinical/clinical research continuum with regard to lymphoma therapies and diagnosis especially via its projects of preclinical development center, its translational research and the reinforcement of its earlyphase clinical trials platform. Meanwhile, CALYM embraces changes in its clinical research via cross-thematic research issues quickly emerging as bioinformatics, molecular diagnosis, real-life data and in silico modeling. These scientific and medical challenges are in line with the interests of established industrial partners or new ones that CALYM identifies in France and abroad thanks to the FINDMED and the GLOBAL CARE Initiative*** consortia respectively. Genomics and biomarkers of lymphoma and solid tumours RNA biology in hematological cancers Microenvironment Cell differentiation, immunology And Cancer (MICMAC) Cytokine receptors and signalling Early steps of haematopoietic transformation Regulation of Bcl2 and p53 networks in multiple myeloma and mantle cell lymphoma U1245 Inserm UMR 1037 Inserm UPS ERL 5294 CNRS, Cancer Research Center of Toulouse UMR U1236 Inserm UMR5235 CNRS, Dynamique des Interactions Membranaires Normales et Pathologiques UMR1170 Inserm, Gustave Roussy Institute UMR892 Inserm 6299 CNRS, Nantes- Angers Cancer Research Center F. Jardin L. Brousset K. Tarte G. Uzé O. Bernard M. Amiot * : see next page ** : see page 15 *** : see page 19 4 INSTITUT in 2016 INSTITUT in

4 II. A STRONG SCIENTIFIC PRODUCTION AND ACTIVITY A STRONG INVOLVEMENT OF RESEARCHERS IN EVENTS ORGANIZATION CALYM contributed to the organization of several scientific congresses in which researchers participated or made an oral presentation. Launch of the first annual European congress in hematology: Focus on lymphoid diseases Paris Lymphomas : Pr. Gilles Salles co-chaired the scientific program, from 4 to 5 November in Paris, France. 6th international workshop on PET in lymphoma, on September, in Menton, France: CALYM was a partner. Symposium organized on 13 September in Paris on Lymphoma Translational Research: some Highlights from CALYM Institute : on the occasion of the arrival in France of Pr. Tak W. Mak from the Campbell Family Institute for Breast Cancer Research at the Margaret Cancer Center University Health Network (Toronto, Canada) to Philippe Gaulard s laboratory at the Mondor Institute of Biomedical Research. 225 STAFF (full time equivalent FTE)) 45 PHD STUDENTS 18 POST-DOCTORAL RESEARCHERS 237 PUBLICATIONS LYSA Days LYSA Days (Journées du LYSA), from 6 to 8 October in Lyon, with 500 participants: CALYM exhibited on a stand shared with LYSA, LYSARC and the European Lymphoma Institute*, Tools to advance lymphoma research. Auvergne Rhône-Alpes cancer competitive cluster Forum, on March in Lyon, France: CALYM held an exhibition stand. 36 CAPACITY TO CONDUCT RESEARCH (FTE) A UNIQUE TRAINING OFFER STRONG COMMITMENT TO SCIENTIFIC CONGRESSES A VERY ACTIVE PARTICIPATION TO INTERNATIONAL CONGRESSES CALYM takes part to scientific international events to advance lymphoma research was once again rich in oral communications and various publications. CALYM researchers were present at the most important international congresses on cancer and/ or hematology: 36 th SFH congress (Société Française d Hématologie), 2016 ASCO annual meeting (American Society of Clinical Oncology), 21 st EHA congress (European Hematology Association), 2 d international conference on New Concepts in B-Cell Malignancies, 10 th International Symposium on Hodgkin lymphoma (ISHL), 58 th ASH annual meeting (American Society of Hematology). In total, 21 oral communications, 13 posters, 2 education sessions and 2 videos were presented by our scientists. THE Lymphoma ACADEMY LAUNCH OF THE LYMPHOMA ACADEMY During the LYSA Days, LYSARC presented the Lymphoma Academy project which aims to propose a training offer for professionals involved or interested in lymphoma R&D. The objective of this offer is primarily, to meet the internal professionalization needs of LYSA, LYSARC, the other entities of CALYM and of the European Lymphoma Institute (ELI *) and, secondly, the needs of their partners on a contract basis. The Lymphoma Academy is based on a highly skilled, dedicated training team of world leading lymphoma experts. It will be available on a web platform in *: ELI ( brings together thirteen European academic groups - including LYSA and LYSARC - specialists in lymphoma within the framework of an institute dedicated to research, training and education on this cancer. They are committed to collaborating together to define strategies to analyze and characterize this cancer, common diagnostic procedures and therapeutic standards, and to facilitate European clinical and basic lymphoma research. 6 INSTITUT in 2016 INSTITUT in

5 SCIENTIFIC FOCUS THE TEAM OF BERTRAND NADEL REWARDED BY THE ARC FOUNDATION The ARC Foundation for Cancer Research awarded a 350,000 grant to Bertrand Nadel s CALYM team, Inserm U1104, for his work on follicular lymphoma. Research works of Bertrand Nadel are part of the call for projects ARC Foundation Labeled Programs. They will ultimately lead to a better diagnosis and a Several CALYM researchers (Olivier Hermine - Inserm U1163 CNRS ERL 8254, Vincent Ribrag - UMR 1170, Steven Le Gouill - Inserm U1232 CNRS ERL6001 Nantes University) are part of the Mantle Cell Lymphoma (MCL) network and help to advance diagnosis and treatment of this cancer. more effective treatment of follicular lymphoma. This project is the counterpart of a research collaboration that has been conducted since 2011 with the American company, MedImmune. (see Two examples of success stories with industry, page 18) ADVANCES IN MANTLE CELL LYMPHOMA OWING TO THE EUROPEAN MCL NETWORK Mantle cell lymphoma is characterized by aggressive progression with a three years median survival and a long-term survival of only about 10%. Because of the limited prognostic power of available biochemical and clinical biomarkers, it has long been impossible to establish a reliable individual risk profile. In this context, clinicians, pathologists and molecular biologists have built and consolidated a European network over the last few years to evaluate innovative therapeutic strategies and study the molecular mechanisms of malignant transformation in MCL. Papers* from the MCL network are published each year in high impact journals. The Olivier Hermine et al. paper**, published in The Lancet, presents the results of a phase III clinical trial showing that high dose addition of cytarabine before autologous stem-cell transplantation in patients aged 65 years or younger with MCL could be considered as a reference treatment. * Minimal residual disease monitoring by 8-color flow cytometry in mantle cell lymphoma: an EU-MCL and LYSA study. Cheminant M. et al. Haematologica Mar;101(3): doi: /haematol Prognostic Value of Ki-67 Index, Cytology, and Growth Pattern in Mantle-Cell Lymphoma: Results From Randomized Trials of the European Mantle Cell Lymphoma Network. Hoster E. et al. J Clin Oncol Apr 20;34(12): doi: /JCO ** Addition of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation in patients aged 65 years or younger with mantle cell lymphoma (MCL Younger): a randomised, open-label, phase 3 trial of the European Mantle Cell Lymphoma Network. Hermine O. et al. Lancet 2016 Aug 6;388(10044): REFRACT-LYMA, THE FIRST COHORT OF MANTLE CELL LYMPHOMA PATIENTS FOR PERSONALIZED TREATMENT In view of the poor prognosis of mantle cell lymphoma, which is still considered as an incurable cancer, the team of Martine Amiot and Steven Le Gouill of Inserm U1232- CNRS ERL6001-Nantes University laboratory, designed a prospective cohort study of patients, REFRACT-LYMA*, to advance research in this field. Today, it is crucial to better understand the underlying biological mechanisms of resistance associated with mantle cell lymphoma (MCL) treatments in order to provide the most appropriate therapy for patients. Collection of tumor samples before launching new therapies and at potential therapeutic failures is required to achieve these goals. REFRACT-LYMA is the first prospective cohort of patients with MCL, collecting biological tumor samples and epidemiological, medical and quality-of-life real life data. All of these data are regularly collected throughout the course of illness from consenting patients. The objective of this cohort is to provide an integrative view of MCL in order to improve clinical management and provide patients with personalized treatments. Histological section of mantle cell lymphoma * The REFRACT-LYMA cohort study: a French observational prospective cohort study of patients with mantle cell lymphoma. Hanf M. et al. BMC cancer (2016) 16:802 CLINICAL RESEARCH IN 2016, FIVE NEW LYSA CLINICAL STUDIES WERE ADDED TO THE SEVENTEEN ONGOING STUDIES RECRUITING PATIENTS BV-ICE Phase I/II feasibility study of brentuximab vedotin, a conjugated anti-cd30 antibody in refractory/relapsed Hodgkin lymphoma patients who are treated by ICE (ifosfamide, carboplatine, etoposide) chemotherapy in second line, and eligible for autologous transplantation. EPI-R-CHOP Phase I/II combination study of tazemetostat, epigenetic modifying agent and R-CHOP (CHOP - cyclophosphamide, doxorubicin, vincristine, prednisone - chemotherapy associating rituximab antibody) in diffuse large B-cell lymphoma (DLBCL) patients in first line, aged 60 to 80 years. LYMA101 Phase II study to evaluate the efficacy of upfront obinutuzumab in mantle cell lymphoma patients treated by DHAP (cisplatin-cytarabine-dexamethasone) chemotherapy followed by autologous transplantation plus obinutuzumab maintenance. SELINDA Phase Ib study of oral selinexor, which inhibits the nuclear transport and R-DHAOx (rituximab plus dexamethasone, high-dose cytarabine, oxaliplatin chemotherapy) or R-GDP (rituximab plus gemcitabine, dexamethasone, cisplatin chemotherapy) in patients with relapsed/refractory B-cell lymphoma. The objective is to determine the dose of selinexor in this association. TRANSPLANT-BRAVE Phase I/II feasibility study combining brentuximab vedotin, an anti CD30 conjugated antibody with DHAP (cisplatin-cytarabine-dexamethasone) chemotherapy in second line Hodgkin lymphoma patients eligible for autologous transplantation. The objective of the phase II is to improve the complete metabolic response at the end of the treatment. 8 INSTITUT in 2016 INSTITUT in

6 FINALIZATION OF THREE LYSA CLINICAL STUDIES RECRUITMENT OF PATIENTS: LAUNCH OF THE CLINTRIAL REFER LYSA APPLICATION RAD001-R Phase I/II trial studying the association of RAD001 (everolimus) and rituximab in patients with non- Hodgkin lymphoma. Results of this study are being submitted. LYMA This open-label randomized phase III study showed that patients with mantle cell lymphoma treated with first line R-DHAP/autologous transplantation followed by rituximab maintenance during three years, had an improved overall survival compared to a simple observation. Oral presentation at the ASH 2016 congress: Rituximab maintenance after autologous stem cell transplantation prolongs survival in patients with mantle cell lymphoma LyMa: a randomized phase 3 trial of the LYSA group. Le Gouill S. et al. Paper that will be very soon published in a high impact journal. LYSA launched at the end of 2016, at its annual congress, the LYSA Days held in Lyon from 6 to 8 October, its smartphone application, ClinTrial Refer LYSA. This new tool aims at accelerating patients recruitment in LYSA clinical studies conducted in LYSA centers in France and abroad. ClinTrial Refer LYSA provides physicians, real-time information on each ongoing LYSA trial, facilitating recruitment of the patients they see during their consultations. Available on ios or Android, this application is completely anonymous and does not store confidential data. This project starting in 2017 is a non-interventional clinical study designed to meet the expectations of pharmaceutical industry in the field of personalized medicine. Evaluated molecular characteristics will be collected with both routine and transfer technologies, in real time, involving a national network of specialized platforms. These characteristics have not only a RT-MLPA GCB-ABC, 14 genes signature prognostic but also a theranostic interest. Indeed, more than fifteen evaluated alterations could make it possible to inform, identify, randomize or stratify populations of DLBCL patients for targeted therapy. Data collected from patient biomarkers may be relevant in case of relapse and may facilitate patients stratification in future phase II trials with novel targeted therapies. * : Real-Time Tailored Therapy REMARC This study showed that DLBCL patients aged 60 to 80 years, treated with R-CHOP and lenalidomide maintenance during twenty-four months had an improved progression-free survival. Oral presentation at the ASH 2016 congress: Final analysis of an international double-blind randomized phase III study of lenalidomide maintenance in elderly patients with DLBCL treated with R-CHOP in first line, the REMARC study. Thieblemont C. et al. Paper published in 2017 in the Journal of Clinical Oncology. DIVERSE SCIENTIFIC RESOURCING PROJECTS RT3*: SETUP OF AN INNOVATIVE PROSPECTIVE REAL-TIME DATA TRIAL Thanks to the Carnot contribution, LYSARC setup in 2016 an innovative trial, RT3, which objective is the real-time molecular characterization of diffuse large B-cell lymphoma (DLBCL) to adapt therapeutic strategies. SEVEN SCIENTIFIC PROJECTS SUPPORTED BY CALYM THANKS TO THE CARNOT CONTRIBUTION Setup of a xenograft model of follicular lymphoma: interest of CD40L - project held by Karine Tarte, UMR 1236 Follicular lymphoma (FL) is an indolent lymphoma (slow evolution) characterized by a strong dependence on a supporting tumor microenvironment, consisting in particular of lymphoid stromal cells, helper lymphocytes TCD4 and macrophages. There is currently no model of FL xenograft due to the dependence of tumor cells on this microenvironment. It drastically limits the possibility of testing new therapeutic molecules in vivo and constitutes a major challenge for industrial partners. The project aims to optimize the xenograft of primary cells of patients with FL in mice, by coinjecting stromal cells. Indeed, the team has previously demonstrated that these cells play a supporting role in the survival of malignant B lymphocytes in vitro and in vivo (i.e. XEMOFOLY project, activity report 2015). However this model does not reproduce the help of TCD4 lymphocytes which is also crucial for tumor growth. The objective of the project is to transduce the stromal cells with the CD40L molecule, thus mimicking a contact with the T lymphocytes, before their use in xenograft. Prospective study of the clonal architecture evolution of chronic lymphocytic leukemia with ibrutinib - project held by Gilles Salles, UMR INSERM 1052 CNRS 5286 About 10% of patients with chronic lymphocytic leukemia have a relapse on ibrutinib therapy due to the emergence of subclones with BTK or PLCG2 enzymes mutations. The analysis of subclones emergence and their dynamics of mobilization, as well as the mutation profile is an important stake to understand resistance emergence mechanisms. However, due to the particular effect of BTK inhibitors which cause an important peripheral lymphocytosis (increase in the number of lymphocytes in the blood), evaluation of this clonal architecture can be assessed from the evolution of subclones, analyzed in the peripheral blood of patients under treatment with BTK inhibitors. The project aims to study the evolution of this clonal architecture. 10 INSTITUT in 2016 INSTITUT in

7 Development and validation of a panel of NGS genes in peripheral T-cell lymphoma - project help by Philippe Gaulard, Inserm U955 The aim of the project is to evaluate a new molecular assay developed by the team for diagnostic and therapeutic purposes, in peripheral T cell lymphomas (PTCL). A panel of about ten genes, selected on the basis of team s data and literature, as being altered in different PTCL entities was developed on a sequencing platform and will be applied to a series of patients with a well clinically annotated PTCL, for which tumor material is available in the LYSA TENOMIC cohort. Gene alterations will be detected with the NGS deep sequencing technique. The panel of genes includes candidate genes for targeted treatments that could benefit PTCL patients. Its diagnostic, prognostic and also predictive relevance of response to specific treatments will be evaluated. Molecular screening of lymphomas treated in phase I - project help by Vincent Ribrag, UMR 1170 This project is in the continuation of the project funded by CALYM in The objective is to offer a better characterization of molecular abnormalities in lymphoid blood diseases in patients who can benefit from a therapeutic trial. The next step is to better characterize these tumors on other possibly associated abnormalities and to characterize potential mechanisms of resistance to these new targeted therapies. The team now has two panels of genes for molecular profiles in most important lymphoma types and chronic lymphocytic leukemia. The next step is to implement Whole Exome techniques to bring out the abnormalities induced by targeted therapies. Analysis of data generated by whole exome sequencing will make it possible to remove scientific locks: to address the concepts of drug secondary resistance for targeted therapies that are being developed at a very early stage and to be able to generate hypotheses that could lead to collaborative works within the CALYM institute. Non-coding RNA biology in lymphomas - project held by Pierre Brousset, UMR 1037 Inserm This project comes in the continuity of an ongoing study (project funded by CALYM in 2014) aiming at improving T-cell lymphoma classification and at finding prognostic/ therapeutic markers and new therapeutic targets. It aims at identifying genetic abnormalities, expression profiles of mrnas and non-coding RNAs in 300 cases of T-cell lymphomas, including anaplastic large-cell lymphomas (PAIR National Lymphoma Project). Oncogenic activation of TAL1 in T-cell acute lymphoblastic leukemia - project held by Bertrand Nadel, Inserm U1104 TAL1 is an overexpressed oncogene in about 40% of T-cell acute lymphoblastic leukemia (T-ALL) cases. For more than half of these TAL1+ leukemia, no obvious genomic alteration of the TAL1 locus is observed, pointing to the existence of unknown mechanisms of dysregulation. In these unsolved TAL1+ cases, expression of TAL1 can be mono or bi-allelic. The team has setup T-ALL xenograft models in immunodeficient mice from human primary cells. Its collection of xenograft models will be completed with mono and bi-allelic TAL1+ T-ALL, and leukemic grafts will be analyzed. Researchers will check expression of TAL1, epigenetic status of TAL1 locus and will characterize possible mutations in proteins of the Polycomb complex which could potentially be at the basis of the bi-allelic activation of TAL1. A number of mono-allelic TAL1+ unsolved cases show a mutation by insertion of a few nucleotides at a specific site, located upstream of the TAL1 promoter. This insertion systematically creates a MYB binding site causing the de novo formation of a super-enhancer structure. The team wishes to exploit this discovery to induce an epigenetic switch. Thus, it undertook to summarize this mutation in various cell lines using CRISPR technology. Then these edited cells will be analyzed and will serve as tools to better understand the introduction/maintenance of epigenetic marks and involved protein factors. Screening of TCR signaling compounds as a new therapeutic approach in PTCL patients - project held by Laurent Genestier, UMR Inserm 1052 CNRS 5286 The T-cell receptor (TCR) is the major signaling mechanism regulating normal T-cells growth. Although its involvement in T-cell lymphomagenesis has not been studied to date, recent evidence suggests that TCR signaling plays a role in human peripheral T-cell lymphoma (PTCL). Moreover, new evidence is provided by two new PTCL mouse models recently setup by the team, in which TCR involvement contributes to the development and survival of PTCL. The main objective of this project is to provide the proof of concept that the use of inhibitors that target TCR signaling compounds may have anti-tumor activity. CEVI_COLLECTION COLLABORATIVE PROJECT THE CEVI COLLECTION INTEGRATES A LYSA CLINICAL TRIAL The CeVi collection includes samples of human viable cells isolated from lymphomas (mainly from lymph nodes) or reactive lymphoid tissues (any tissue or fluid, site of a potential tumor proliferation). These rare samples, associated with biological and clinical databases, make it possible to CALYM teams to develop new in vitro and in vivo lymphoma models, to study the tumor microenvironment or to identify new blood and tissue biomarkers. Results of these researches offer opportunities for collaborative research with external partners. In 2016, the CeVi collection was requested twice to provide complementary biological material to ancillary studies of LYSARC clinical trials. Moreover, it took a new step by integrating a first LYSARC clinical trial as soon as it was designed. This pilot project for CeVi will be structuring and an innovative source of material for researchers. All CeVi platforms are involved and are organized to launch the Ento-R-CHOP project, planned for mid CEVI KEY FIGURES ON 31/12/ samples 3370 tubes 12 INSTITUT in 2016 INSTITUT in

8 III. DEVELOPMENT OF PARTNERSHIPS Evolution of the number of contacts with companies since contacts were made with companies in 2016, 84% with mid-market companies, SMEs and small offices/ home offices. They resulted in twenty scientific collaboration proposals. KEY FIGURES OF PARTNERSHIP RESEARCH DISTRIBUTION OF REVENUES BY TYPES OF RESEARCH ACTIVITIES The revenue generated in 2016 by CALYM is derived from five types of activities: Contract research that consists of research activities conducted in partnership with worldwide socio-economic stakeholders, in response to their needs Non socio-economic contract research: contract research based on a direct research contract with a partner who does not fit in the Carnot contribution base Collaborative research that represents research projects funded by the government (state, local authorities, national agencies, European funds...) Technical services License fees on intellectual property: licences, sale of patents Contract research within the socio-economic world Contract research without the socio-economic world Collaborative research Technical services License fees on intellectuel property Most of our proceeds correspond to contract research with socio-economic stakeholders. In 2016, licenses on our databases which are based on our clinical trials generated 9% of our proceeds for 1.78 million. Key figures of intellectual property Total number of priority patents filed in Total number of priority patents in portfolio 48 License fees ( M) on intellectual property 1,78 STRONG RELATIONSHIPS WITH OTHER CARNOT INSTITUTES AND THE NETWORK CARNOT ANR-15-CRNT-0007 FILIERES FINDMED The official launch of this action aiming at structuring the Carnot institutes offer in response to the needs of life science companies, took place at the meeting of 15 January 2016 in Paris. The three focus of development of FINDMED that were presented are the following: DEVELOPMENT OF FINDMED CALYM with nine other Carnot institutes won in 2015 the Valorisation-instituts Carnot call for projects within the framework of the program of Investments for the Future operated by the French National Research Agency (ANR). Thus, the FINDMED consortium dedicated to Health-Medicines was born. construction of a coordinated and structured innovation offer to meet the challenges and needs of the Health/Medicines sector, development and organization of networks of equipment and platforms, development of short-term R&D projects with midmarket companies and SMEs that do not or rarely use public research and which ambition is to develop long-term collaborations with strong potential for innovation. 14 INSTITUT in 2016 INSTITUT in

9 The operational team of FINDMED gradually formed following the appointment of its director, Damien Salauze in February. A consortium agreement was signed between the various Carnot institutes at the end of July 2016 in order to define precisely how the consortium will operate and the organization of relationships between members. The technological platforms of the institutes which combine cutting-edge equipment and know-how, have been the subject of a structured offer to meet the innovation needs of SMEs. This offer is now available on the FINDMED website ( through research collaborations or provisions of services. *: FINDMED is the result of the grouping of six Carnot institutes**, which core business is (human or animal) health, joined by four other Carnot institutes*** that provide complementary technical skills required for R&D programs in the field of Health (ICT, chemistry, galenics). ** : CALYM, Curie Cancer, ICM, France Futur Élevage (ICSA), Pasteur MS, Voir et Entendre ***: CEA LIST, Chimie Balard Cirimat, Inria, M.I.N.E.S CALYM ACTIVELY CONTRIBUTES TO THE DESIGN AND IMPLEMENTATION OF THE STRATEGY OF THE CARNOT INSTITUTES CALYM operational team took part to various meetings and events organized by the network (Ai Carnot) Rendez-Vous Carnot, 5-6 October 2016, to make institutes visible and to facilitate the search for industrial partners. Eight face-to-face meetings were held during these days for CALYM. Working groups and seminars to seek solutions and to share good practices between institutes. Board of directors and plenary meetings of the Carnot institutes network to collect and share information. FINDMED and CALYM at the event of the Carnot institutes On 6 July 2016, the Carnot institutes network organized the event, its annual meeting for industry partners. Companies, laboratories, institutions, actors of the research and innovation world gathered and exchanged on the theme Industrial transformation through innovation - Carnot institutes are mobilized to serve mid-market companies and SMEs. On this occasion, in the exhibition area, the participants could meet the managers of the eight Carnot sectors: Aerospace, Fashion and Luxury, Automotive, Eco-industries/ Renewable Energies, Extractive Industries and Primary Processing, Consumer Goods/Sport & Wellness, Mechanical industries and Processes, Health/Medicines. FINDMED was represented as well as CALYM. HIGHLIGHT: CALYM S THIRD SCIENTIFIC AND PARTNERSHIP DAY ADVANCING LYMPHOMA DIAGNOSIS & TREATMENT TOGETHER CALYM s third scientific and partnering day for its industrial partners, took place 17 October 2016 in Paris. This international event, rich in interactions allowed researchers and clinicians of the institute to present their new lymphoma R&D offering and latest research results to an audience of more than 110 people including 36 industry representatives, from pharmaceutical, biotechnology, diagnosis and imaging companies such as ABBVIE, BAYER, BioOncology Genentech, Boehringer Ingelheim, CELGENE, GILEAD, IPSEN, JANSSEN, KEOSYS, MSD, NovImmune, ONXEO, PFIZER, ROCHE, TAKEDA, ULTIVUE, etc. The program of the day was divided in three main sessions: Therapeutic targets and in vitro research In vivo and clinical research Biomarkers Two representatives of large pharmaceutical companies were invited to bring their industrial vision. Marc de Garidel, chairman of IPSEN and chairman of the Board of The Innovative Medicines Initiative, presented his thoughts and successful experience of academyindustry research partnerships. Ken Takeshita, vice-president of CELGENE presented mutual benefits for academy and industry to collaborate together on clinical study projects in the lymphoma field. In particular, he pointed out the experience of his company with LYSARC that has been sponsor of ten CELGENE trials since During the networking breaks, posters presenting research activities and R&D offer of CALYM teams were displayed to facilitate exchanges between the participants. They are now available as a booklet for download on CALYM s website. International strategy of the Carnot institutes network (Ai Carnot) CALYM also contributed directly to the implementation of the strategy of international development of Ai Carnot through its general manager Pascal Deschaseaux, as vice-chairman of Ai Carnot in charge of international affairs. Relations were established in March 2016 with companies in Australia and New Zealand during the travel of a French delegation led by the MEDEF ( Movement of the Enterprises of France ), to which Ai Carnot and CALYM participated. The Carnot network was presented to major Australian research and innovation players including the Group of Eight of the first eight Australian universities. 16 INSTITUT in 2016 INSTITUT in

10 INTERNATIONAL DEVELOPMENT CALYM conducts a large part of its partnership research activity with international companies, in particular major pharmaceutical groups. In order to find new potential partners, the institute participates in major international business conventions. Geographical distribution of contacts in 2016 CANADA 3 EUROPE (APART FROM FRANCE) 29 In 2016, CALYM was present at BIO Europe Spring from 4 to 6 April 2016 in Stockholm, Sweden, at BIO international convention from 6 to 9 June in San Francisco, USA, at BIO Japan from 12 to 14 October in Yokohama, Japan and at BIO Europe from 7 to 9 November in Cologne, Germany. Forty-five industrial contacts were made at these various events. FRANCE 21 ISRAEL 1 INDIA 1 CHINA 1 Actions of partnering development, targeted towards Europe, the United States and Asia, were pooled to increase the striking force of the institutes. In January 2016, the consortium had three international locations in San Francisco, Boston and Seoul, while maintaining coordination in Paris and resources for European prospecting. GLOBAL CARE was very positively perceived by industry who appreciated the sharing aspect and the one-stop shop. The action of the business developers team made it possible to meet physically about 40% of the Asia/Europe/USA market of biotech companies and pharmaceutical groups. These meetings generated 888 contacts and allowed to establish 254 direct contacts between industry representatives and the institutes, which represents, in the space of two and a half years of effective action, an average of 8 connections per month. In total, a network of 1148 high-level personal contacts - President, CEO and CSO - was established. For CALYM this represented 149 contacts and 41 connections. In addition to international partnerships development, the consortium was also at the center of the Carnot filières Health - Medicines application with the FINDMED project, which made it possible to strengthen links with the Carnot institutes in health related fields and to develop prospecting at the national level as a logical complement to GLOBAL CARE. Another notable achievement of GLOBAL CARE was the organization of the French American Innovation Days (FAID) 2016 in Cambridge, USA, on 9 and 10 February (see article below). The GLOBAL CARE brand is now recognized and it is therefore, enriched by the various teachings, successes and in full control of the methods, that the consortium wants to preserve the dynamics created. SOUTH KOREA 2 JAPAN 5 USA 19 TAIWAN 2 FRENCH AMERICAN INNOVATION DAYS 2016: A BEAUTIFUL SHOWCASE OF FRENCH R&D IN LIFE SCIENCES! Distribution of contract revenues with socioeconomic world NUMBER OF CONTRACTS AMOUNT OF REVENUES ( ) NUMBER OF COMPANIES NATIONAL COMPANIES FOREIGN COMPANIES Half of the contracts in France and abroad relates to preclinical research, while the other half to Phase I to III clinical trials. Most of our research contract proceeds are spent abroad with big pharmaceutical companies, in particular to conduct international Phase III clinical trials in collaboration with LYSA-LYSARC. GLOBAL CARE INITIATIVE, A VERY POSITIVE ASSESSMENT On 9 and 10 February 2016, CALYM participated in the French American Innovation Days (FAID), organized by GLOBAL CARE, in collaboration with the French Embassy in the United States, at the MIT Media Lab in Cambridge (USA). This 2016 edition focused on Precision medicine & new technologies: transformed clinical research. In the heart of the world s first biocluster, the event brought together nearly 350 French and American participants - academic researchers, industry representatives, investors, representatives of incubators and regulatory authorities - to discuss recent developments in biomedical research, the expertise field of both countries. The GLOBAL CARE project The Global Partnering Research Initiative of the Carnot Human Health Institutes, selected under the call for projects Carnot International, within the framework of Investments for the Future, was set up in It brings together the five Carnot human health institutes: CALYM, Pasteur MS, Curie Cancer, ICM and Voir & Entendre around a common objective: the increase of partnering R&D of each institute, carried out abroad, through coordinated international actions. These actions revolved around two dimensions: development of partnerships and R&D. On the R&D side, GLOBAL CARE brought a real dynamics of exchange and sharing of good practices within the consortium, in addition to the common operational achievements on the spot. The founders and managers of the five Carnot human health institutes, a delegation of leading scientists from the consortium and representatives of SMEs, presented together the French expertise and the partnership capacity of GLOBAL CARE, thus displaying a joint international ambition. Carnot institutes, along with their partners, the Medicen and Lyonbiopôle competitiveness clusters, and the Massachusetts government agency to support the bio-medical industry - the Massachusetts Life Science Center -, could exchange and/or maintain already MIT Media Lab in Cambridge (USA) existing connections with leaders of pharmaceutical industry, biotechnology, imaging and also ICT companies. In addition, FAID 2016 made it possible to present Europe and in particular France, as a strategic stage of clinical developments. Many contacts were initiated, leading to high-level transatlantic international collaborations. For more information: 18 INSTITUT in 2016 INSTITUT in

11 TWO EXAMPLES OF SUCCESS STORIES WITH INDUSTRY PREVENTION AND EARLY TREATMENT OF FOLLICULAR LYMPHOMA: A SUCCESSFUL PARTNERSHIP BETWEEN MEDIMMUNE AND BERTRAND NADEL S TEAM PRECLINICAL DEVELOPMENT OF OBINUTUZUMAB: A LONG-TERM PARTNERSHIP BETWEEN PR. CHARLES DUMONTET S TEAM AND ROCHE/GLYCART The work of Bertrand Nadel s team at the Marseilles- Luminy Immunology Center on a better understanding of lymphomagenesis in follicular lymphoma was the subject of a research collaboration agreement with MedImmune, the global biologics research and development arm of AstraZeneca, from 2011 to 2016*. Follicular lymphoma (FL), the second most common B-cell lymphoma in adults in western countries, is often characterized by an asymptomatic indolent clinical course over several years. Therefore, the diagnosis is frequently delayed and the treatment is carried out on a largely disseminated tumor. Despite the therapeutic progress of the last years, this cancer remains incurable. Treated patients relapse quickly and Histological section become resistant to treatments or have of follicular lymphoma their disease progress to an aggressive form of diffuse large B-cell lymphoma. The prevention and treatment of this type of lymphoma is largely dependent on the identification of early biomarkers and innovative therapeutic approaches targeting early stages of disease development. This was the goal of the collaborative project set up by Bertrand Nadel s team with the company Medimmune and entitled Identification of proliferative lymphoma progression biomarkers and novel therapeutic candidates for early antitumor intervention. This project was supported by a large European cohort - the European Prospective Investigation into Cancer and Nutrition Cohort (EPIC) - of more than 520,000 healthy participants (at recruitment) who were followed for more than 15 years. Patients for whom the diagnosis of follicular lymphoma was made during this period were selected for this study. Patients with FL present in their genome a mutation corresponding to a reciprocal exchange of genetic material between chromosomes 14 and 18. This translocation t(14;18) leads to an abnormal production of the BCL2 oncogenic protein. This molecule, called anti-apoptotic, contributes to prolonged cell survival by reducing its capacity to self-regulate, and leads to a cascade of secondary events leading to the development of cancer. The translocation t(14;18) is detectable in the blood of healthy people but in very small amounts. The analysis of patients with FL in the EPIC cohort revealed an abnormally high frequency of translocation t(14;18) in their blood, years before the diagnosis of their cancer. The study also showed that the B cells with this translocation constitute an exponential clonal population of atypical B cells, which show a combination of genotypic and phenotypic features of FL. Finally, the researchers were able to validate that the pre-clonal clone was indeed the one responsible for the tumor. The positive t(14;18) circulating clones can thus be considered as precursor cells (CPCs) already involved in the development of FL up to more than 10 years before the clinical manifestation of the disease. The individual differences in their frequency, in the blood reflect different stages of progression in the causal chain of events leading to the development of lymphoma. Importantly, these CPCs could also be the cause of recurrent relapses of the FL, relapses currently constituting one of the major medical stakes of this incurable cancer. The next steps of the project were to genetically characterize these CPCs in the blood samples of the EPIC cohort and to identify the key factors associated with translocation t(14;18) which lead in some subjects to the appearance of this cancer. Candidate genes were identified and a preclinical mouse model of FL was developed by the team to validate in vivo candidate genes that could constitute novel therapeutic targets. This highly exploratory partnership project led to real advances in the understanding of lymphomagenesis and resulted in several publications in high-impact journals such as the Journal of Clinical Oncology (Roulland S. et al. 1,32 (13): , May 2014) or the Journal of Clinical Investigation (Sungalee S. et al., 124 (12): , Dec 2014) where MedImmune partners are co-authors. The project will be continued beyond 2016 thanks in particular to the support of a 350,000 grant from the ARC Fondation. *: This project was also supported by the Fondation de France, the Association for Cancer Research, Inserm, CNRS, ITMO Cancer, France Lymphome Espoir. Pr. Charles Dumontet s Anticancer Antibody team from the Cancer Research Center of Lyon has collaborated for a decade with Roche/ Glycart for the development of new therapeutic antibodies against non-hodgkin lymphomas. The reference treatment that has revolutionized the management of non-hodgkin lymphoma (NHL) is the anti-cd20 type 1 antibody, rituximab in combination with chemotherapy. However, indolent lymphomas (asymptomatic slow development) such as follicular lymphoma are still incurable with a high proportion of relapsed patients with diffuse large B-cell lymphoma (DLBCL). In the early 2000s, Roche/Glycart developed a novel humanized anti-cd20 type II antibody, obinutuzumab or GA101 to complete the therapeutic arsenal against NHL. The mechanism of action of this new antibody and its preclinical anti-lymphoma activity were studied in collaboration with Charles Dumontet s team. The researchers showed that GA101 was more potent alone or in combination with cyclophosphamide than rituximab in vitro and in vivo in follicular lymphoma cell lines xenograft mouse models. In addition, GA101 was found to be more effective than rituximab and ofatumumab, another type 1 anti-cd20 antibody in DLBCL xenograft mouse models. The mechanism of action of GA101 differs from that of rituximab in that it induces more direct cell death and is involved to a limited extent in complement-dependent cytotoxicity (CDC). GA101 was modified by glyco-engineering to increase its affinity for receptors of immune effector cells (natural killer cells, macrophages, monocytes) recruited into antibody dependent cellular cytotoxicity and phagocytosis (ADCC and ADCP). The researchers showed that GA101 activates this cell destruction pathway more strongly than rituximab. The stimulation of this mechanism could be important especially for patients who carry a low affinity allele of their receptor. Results of these studies led to several scientific publications and the filing of a patent*. They naturally led to the setting up of clinical trials comparing the activity of GA101 with other treatments. Obinutuzumab is marketed in France since 2014 under the name Gazyvaro to treat chronic lymphocytic leukemia. Since 2016, combined with bendamustine in induction, followed by maintenance therapy by Gazyvaro, is indicated in patients with follicular lymphoma in case of non-response or progression, during or within six months of treatment including rituximab. The collaboration between Charles Dumontet s team and Roche/Glycart goes on today around this drug and the interactions that it can generate. * : Publications: Dalle S. et al. Mol Cancer Ther Jan;10(1): / Herter S. et al. Mol Cancer Ther Oct;12(10): Patent: ROCHE GLYCART AG, Dumontet Charles, Friess Thomas, Herting Frank, Klein Christian, Umana Pablo (WO ). Use of a type II anti-cd20 antibody with increased antibody dependent cellular cytotoxicity (ADCC) in combination with cyclophosphamide, vincristine and doxorubicin for treating non-hodgkin s lymphomas. WO/2009/118142, PCT/EP2009/002111, Application 23/3/ INSTITUT in 2016 INSTITUT in

12 CONTACTS Véronique STANIEK Director of Operations Tel (0) OUR GUARDIANSHIPS Partnering research partnering@calym.org 22