Cytotherapy 22 (2020) 1 5 Contents lists available at ScienceDirect CYTOTHERAPY journal homepage: www.isct-cytotherapy.org REVIEW Spanish Cell Therapy Network (TerCel): 15 years of successful collaborative translational research Fermín Sanchez-Guijo1, Damia n García-Olmo2, Felipe Pro sper3, Salvador Martínez4, 5 Agustín Zapata , Francisco Ferna ndez-Aviles , Juan Jose 6  Toledo-Aral7, Miguel Torres8, Isabel Farin 9  n , Jose ~ as , Lina Badimo 10  Luis Labandeira-García11, Javier García-Sancho12,  M. Moraleda13,*, on behalf of TerCel Jose 1 Servicio de Hematología, IBSAL-Hospital Universitario de Salamanca, CIC y CIBERONC, Universidad de Salamanca, Salamanca, Spain 2 “Fundacio n Jimenez Diaz” University Hospital, Universidad Autonoma de Madrid, Madrid, Spain 3 Servicio de Hematologia y Terapia Celular, Clinica Universidad de Navarra y CIMA, Universidad de Navarra, Pamplona, Spain 4 Instituto de Neurociencias UMH-CSIC, CIBERSAM, San Juan de Alicante, Alicante, Spain 5 Department of Cell Biology, Complutense University, Madrid, Madrid, Spain 6 Servicio de Cardiología, IiSGM-Hospital General Universitario Gregorio Maran ~o n, Universidad Complutense, CIBERCV, Madrid, Spain 7 Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain 8 Cardiovascular Development Program, Centro Nacional de Investigaciones Cardiovasculares, CNIC, Madrid, Spain 9 Departamento de Biología Celular, Biología Funcional y Antropología Física, Estructura de Recerca Interdisciplinar en Biotecnologia i Biomedicina (ERI BIOTECMED), and CIBERNED, Universidad de Valencia, Valencia, Spain 10 ICCC Program, IR-Hospital de la Santa Creu I Sant Pau, Autonomous University of Barcelona, Barcelona, Spain 11 Research Center for Molecular Medicine and Chronic Diseases (CIMUS), University of Santiago de Compostela and Networking Research Center on Neurodegenerative Diseases (CIBERNED), Santiago de Compostela, Spain 12 Instituto de Biología y Genetica Molecular (IBGM), Universidad de Valladolid, Valladolid, Spain 13 Servicio de Hematología, Hospital Clinico Universitario Virgen de la Arrixaca, IMIB, Universidad de Murcia, Murcia, Spain A R T I C L E I N F O A B S T R A C T Article History: In the current article we summarize the 15-year experience of the Spanish Cell Therapy Network (TerCel), a Received 30 April 2019 successful collaborative public initiative funded by the Spanish government for the support of nationwide Accepted 1 November 2019 translational research in this important area. Thirty-two research groups organized in three programs devoted to cardiovascular, neurodegenerative and immune-inflammatory diseases, respectively, currently Keywords: form the network. Each program has three working packages focused on basic science, pre-clinical studies cell therapy and clinical application. TerCel has contributed during this period to boost the translational research in cell regenerative medicine therapy in Spain, setting up a network of Good Manufacturing Practice certified cell manufacturing facili- research network ties and increasing the number of translational research projects, publications, patents and clinical trials of stem cells the participating groups, especially those in collaboration. TerCel pays particular attention to the public-pri- translational medicine vate collaboration, which, for instance, has led to the development of the first allogeneic cell therapy product approved by the European Medicines Agency, Darvadstrocel. The current collaborative work is focused on the development of multicenter phase 2 and 3 trials that could translate these therapies to clinical practice for the benefit of patients. © 2019 International Society for Cell and Gene Therapy. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license. (http://creativecommons.org/licenses/by-nc-nd/4.0/) Introduction clinicians and also the general population. The therapeutic potential of cells for a number of degenerative and/or severe diseases that currently In the last two decades, the emerging field of regenerative medicine lack a definitive treatment has prompted many private and public initia- and cell therapy has drawn the attention of many basic researchers, tives worldwide, especially in the USA and Asian countries [1,2]. The European Union (EU) has the advantage of a common regulatory framework and the existence of the hospital exemption * Correspondence: Prof. J.M. Moraleda, MD, PhD, Servicio de Hematología, Hospital rule for the administration of advanced therapies medicinal Clínico Universitario Virgen de la Arrixaca, Ctra. Madrid-Cartagena, El Palmar 30120, products (ATMPs). However, this background has fostered single- Murcia, Spain. E-mail address: jmoraled@um.es (J.M. Moraleda). institution based experiences and small phase 1 and 2 clinical trials https://doi.org/10.1016/j.jcyt.2019.11.001 1465-3249/© 2019 International Society for Cell and Gene Therapy. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license. (http://creativecommons.org/licenses/by-nc-nd/4.0/) 2 nchez-Guijo et al. / Cytotherapy 22 (2020) 1 5 F. Sa Table 1 scientific output, competitive funding and areas of research. The pro- ATMPs in Europe that obtained MA. grams are evaluated yearly and the scientific goals of the different Product Disease Holder of MA Y programs have been revisited in 2006, 2012 and 2016. TerCel started with eight groups in 2003, and the number increased to 31 in 2006, ChondroCelect Cartilage disease Tigenix 2009a when new research groups were incorporated to the network based Glybera Type 1 hyperlipoproteinemia UniQure 2012a MACI Cartilage disease Aastrom 2013a on their expertise and ability to demonstrate competence and collab- Provenge Prostate cancer Dendreon 2013a oration. Thereafter, the number of research groups has remained sta- Holoclar Corneal disease Chiesi 2015 ble (between 31 and 33) to date, when 32 research groups are Imlygic Melanoma Amgen 2015 included in the network (10 in CardioCel and 11 in both NeuroCel Strimvelis Severe combined GSK 2016 inmmunodeficiency and OshiCel). The total number of investigators is currently 351, with Zalmoxis Hematopoietic transplantation MolMed 2016 31 directly sponsored by TerCel (11 PhD investigators, 12 graduate Spherox Condral lesions CO.DON 2017 students and 8 technicians). Alofisel Perianal fistula in Crohn’s disease Takeda 2018 There are six major strategic objectives of the network (Figure 1): Kymriah Acute lymphoid leukemia and Novartis 2018 (i) to understand the mechanisms of repair and the regenerative prop- diffuse large B-cell lymphoma Yescarta Diffuse large B-cell lymphoma and Kite 2018 erties of grafted and endogenous stem cells in tissues and organs, as primary mediastinal B-cell well as the role of the niche in regulating their function; (ii) to improve lymphoma stem cell functionality using new technologies such as cell engineering EMA, European Medicines Agency, MA, marketing authorization. or gene editing; (iii) to develop in vitro and in vivo disease models to a MA was withdrawn or suspended by the EMA afterward due to different reasons. get safety and efficacy proof-of-concepts of these improved cell thera- pies; (iv) to design and improve protocols for the isolation, manipula- instead of a coordinated approach leading to large phase 2 and 3 tri- tion, expansion, storage and administration of cells for clinical use als, at least at the national level. It is clear that collaborative efforts in under Good Manufacturing Practice (GMP) conditions; (v) to develop this new area of translational research will be needed to achieve the collaborative multi-centric clinical trials to translate these therapies to global aim of transferring these treatments from the bench to the the clinical practice for the benefit of patients; and (vi) to design and bedside within the shortest possible time [3,4]. But, as indicated, launch programs for rigorous dissemination of cell therapy knowledge there are only a small number of published phase 3 trials and very to society and fight against the fraud in this field. few cell therapy products have reached the final process of authoriza- Each program has a pipeline of three working packages (WPs) tion by the regulators. As of June 2018, there are only three cell prod- aiming at specific objectives, deliverables and milestones to identify ucts of 12 ATMPs approved for marketing in Europe (Table 1). It cells and ATMPs of benefit in the treatment of human diseases. The should be noted that approval of ATMP in the EU has a number of first WP of each program (WP1, or basic research WP) is devoted to inherent difficulties, based on quality issues and the evaluation of basic science and mostly includes in vitro analyses and understanding post-marketing risk management [5]. of molecular mechanisms. WP2 (pre-clinical WPs) are focused on In this article we summarize the 15-year experience of the Span- pre-clinical studies of stem cell administration in animal models of ish Cell Therapy Network (TerCel), a successful collaborative public diseases of the corresponding area. WP3 (clinical WP) involves all the initiative funded by the Instituto de Salud Carlos III (ISCIII), the stages of clinical application of cell products, from cell production agency of the Spanish government for the support of nationwide under GMP conditions to first-in-human clinical trials and advanced translational research in health sciences. collaborative clinical trials. Description and Objectives of TerCel Management and Regulations of TerCel TerCel was established in 2003 with the aim of promoting transla- TerCel belongs to a wide program of disease-oriented research net- tional research in cell therapy bringing together both basic research works (RETICs, Thematic Networks for Cooperative Research in Health) groups and clinical investigators with a common interest in this area. At that time, they were very few experiences in Europe organized through the National Health System research structures to coordinate stem cell research and cellular therapy at the national level. Cur- rently, there are structures similar to TerCel in other EU countries, but each one with their own peculiarities based on the way the trans- lational research has been established in that country. For example, in France they have developed ECell France for Regenerative Medicine (created in 2012), in Italy the Instituti di Ricovero e Cura a Carattere Scientifico (IRCCS) established a number of structures for cell produc- tion and regenerative medicine research starting in 2000, the Medical Research Council and other members of the UK Regenerative Medi- cine Funders Forum had initiatives as the UK Regenerative Medicine Platform (2013) or the Cell Therapy Catapult (2012) and The Nether- lands Institute of Regenerative Medicine was established in 2009, among others. It could be of interest, although it is out of the scope of this article, to compare these platforms and structures not only in terms of their characteristics but also of their outcomes. The work of the TerCel consortium is organized in three main healthcare areas: neurodegenerative diseases (NeuroCel program), cardiovascular diseases (CardioCel program) and inflammatory, immunologic and metabolic diseases (OshiCel program). Research groups throughout the nation joined the network based on an independent evaluation of their background in terms of Fig. 1. Scientific strategy of TerCel. nchez-Guijo et al. / Cytotherapy 22 (2020) 1 5 F. Sa 3 funded by the ISCIII. Every 4 years there is a specific competitive call groups was 6.5. Nevertheless, this is indeed still an IF value that for scientific collaborative proposal applications by the programs of reflects the challenge of publishing translational research studies every RETIC, which compete among them for financial support based with a low or medium number of patients in high-impact journals, on a thorough external and independent evaluation. although the results may be important to further develop the field TerCel is led and coordinated by a Managing Executive Committee (as it was during the early years of TerCel). It has to be acknowledged (MEC), which is composed of the network general coordinator, the that this fact has further negative consequences for getting additional coordinator of each program (CardioCel, NeuroCel and OshiCel) as funding within universities or from other financing structures includ- well as the coordinators of each of the three (basic, pre-clinical and ing the European Commission. clinical) WPs in each program. The tasks of MEC are as follows: (i) to In this same 2013 2017 period, the total number of competitive supervise the advances of the WPs and the accomplishment of deliv- research projects in which TerCel groups were involved was 487. erables and milestones; (ii) to administer the funding received from Seventy of them were the result of collaborations between groups of the ISCIII; (iii) to foster the scientific collaboration among research the network, and in 61 only TerCel members were involved. The total groups; (iv) to discuss and design the scientific strategy; (v) to sup- amount of financial support for these TerCel research projects in this port the investigators in the preparation of scientific meetings and period was 144,169,242€. scientific evaluations; (vi) to guarantee the adequate dissemination The education program in this period has promoted and financed of the results obtained both to the scientific community and to the a median of ten workshops a year related to ATMP therapies and a general public; and (vii) to establish scientific subcommittees to median of three young investigator exchanges among TerCel groups. address specific work priorities. In this last task, TerCel has created The most important achievements of TerCel in its path from bench several platforms and scientific subcommittees dedicated to the stan- to bedside have been the initiation of clinical trials involving ATMPs. dardization of common protocols for basic research, to establish com- Between 2013 and 2017, TerCel groups initiated a total of 111 clinical mon animal models of diseases and uniform cell production protocols trials. Of them, 28 were developed in collaboration with TerCel under GMP conditions, to biobank pluripotent stem cell lines accord- groups and in 22 only groups from the network participated. This is ing to the legislation, to facilitate the exchange of investigators quite an achievement because the public financial support for clinical between research groups, to interact with the Spanish Medicines research in this period was very low due to the country’s economic Agency (which will be discussed later) and a very important one crisis [7]. Before the crisis, Spain was the leading European country in focused on defining Good Clinical Practices in Cell Therapy. Indeed, terms of number of funded ATMP clinical trials [8]. This was due to the Good Clinical Practices in Cell Therapy committee mission is to an important financial support from the ISCIII to non-commercial clarify all the questions relevant to the patients who are offered cell clinical research and to the starting of the TerCel Network in the therapy treatments (there is a specific section in TerCel website more salutary period 2004 2010 [8]. More recent research in the devoted to this [6]) and to identify illegal and fraudulent offers of cell database clinicaltrials.gov [9] searching trials on “cell therapy” or therapies in our area of influence. Regarding the GMP facilities “stem cells” between 2011 and 2018 shows that Spain is the second platform, each GMP facility shares with the others the academic country in Europe in number of clinical trials (68 trials), just after investigational medical product dossiers and its knowledge for Ter- France (95 clinical trials). Cel-initiated collaborative clinical trials, but some of them are also Apart from considering all these achievements, with several suc- participating in industry-sponsored trials (where some of the cessful experiences as the development of Darvadstrocel that will be manufacturing process could be partially externalized) and in multi- discussed next, there are a number of pitfalls and lessons learned by center European clinical trials (where they are either responsible for TerCel throughout this 15-year journey, especially when coordinating the production or partners in this process). Funding of the all these academic research groups in an over-bureaucratized public manufacturing by TerCel GMP facilities is always included in the proj- system from different regions with sometimes different research ect budget for competitive national and EU grants. structures. Probably the need of early collaboration to develop the pre- TerCel has also an Internal Scientific Advisory Committee, formed clinical experiments and cooperation in the design of the clinical trials by all principal investigators of the research groups, and an External is one of the most important learnings. We have faced scarce knowl- Scientific Advisory Committee, integrated by four internationally edge in ATMP trials by Contract Research Organizations when we renowned experts in stem cell research and cell therapy. Finally, the started, and their cost remains excessive compared with the budget General Assembly, formed by all the investigators of the network, generally obtained to perform clinical trials with ATMPs. Moreover, meets once a year at the TerCel Annual Scientific Meeting. TerCel also although public-based Contract Research Organization platforms have organizes an Annual Technical Workshop meeting open to the public, been developed in Spain (e.g., CAIBER and later SCReN platform), their where internal investigators and/or external experts discuss technol- work is sometimes limited by scarce budget and personnel. For us, it ogy-related advances around a specific topic selected by the MEC has been also essential to approach the regulatory agencies in a very each year (e.g., Chimeric Antigen Receptor T cells, organoids, biofabri- early stage of the development of the project. Training in regulatory cation). The goal is to analyze in detail emerging concepts in the field science in ATMPs is a clear “unmet need” in our scientific and clinical and to raise public awareness on the advances at the forefront of cell environment. In this regard, we have to stress that the collaboration therapy research. with the Spanish Medicines Agency (AEMPS) has been crucial to obtain many of TerCel’s achievements. In this regard, TerCel investigators Main Achievements of TerCel have established regular meetings with AEMPS representatives to dis- cuss common problems and areas of interest, and AEMPS has been When analyzing the period 2013 2017, the number of publica- extremely open to implement the rules to obtain good-quality ATMP tions of TerCel investigators add up to 1303, with a median of products, giving scientific and technical advice in clinical trial applica- 260 manuscripts/year. Of the total number, 209 manuscripts were tion and being rigorous but constructive in the inspections of the GMP the result of collaborative efforts of at least two groups of the net- facilities, among other interactions with the network. work, and 140 manuscripts had all authors exclusively from TerCel groups. Therefore, collaboration between groups clearly fostered the TerCel and a Case of Successful Public-Private Collaboration in generation of synergies that resulted in more and higher impact Spain: Darvadstrocel manuscripts. In this regard, the median impact factor (IF) of all manu- scripts published by TerCel members in this period was 4.9, whereas Darvadstrocel (named Cx601 during drug development, and now the IF of the articles published in collaboration between TerCel commercially known as Alofisel) is the tenth ATMP approved in the EU 4 nchez-Guijo et al. / Cytotherapy 22 (2020) 1 5 F. Sa under this definition (Table 1) and the first cell therapy based on allo- It is clear that with the GMP facilities network built, the collabora- geneic cells [10,11]. This product is based on adipose tissue derived tive experience acquired and the partnerships established with some mesenchymal stromal cells (MSCs) and its labeled therapeutic indica- biotechnological and pharmaceutical companies, the current situation tion is for the treatment of complex perianal fistulas in adult patients should foster the development of new academic-based cell products in with nonactive/mildly active luminal Crohn’s disease, when fistulas more applications. Because for some indications they may co-exist have shown an inadequate response to at least one conventional or with commercial ATMPs, it will be important to find clinical settings biologic therapy [12]. Its efficacy was demonstrated in a randomized and technological challenges where both strategies may become syn- phase 3 clinical trial, in which the primary endpoint was a strict com- ergic and avoid competition. bined remission outcome at week 24 (i.e., clinical assessment of clo- sure of all treated external openings that were draining at baseline, Conclusion and absence of collections >2 cm of the treated perianal fistulas con- firmed using masked central magnetic resonance imaging) showed In summary, the Institute of Health Carlos III approach to promote that the experimental arm (Cx601) provided significantly better cell therapy in the Spanish national health system through the TerCel results than placebo (50% versus 34%; P = 0.024), with no differences network has proven to be successful. It has provided a framework for in secondary effects (anal abscesses and proctalgia) [13]. These results scientific interaction and for the promotion of translational research. were further confirmed with a longer follow-up [14]. The interesting TerCel has demonstrated that these new therapies can be safely issue with this product is that the initial idea started back in 2002 in translated to the patients, the feasibility of performing collaborative one of the TerCel groups in Madrid (located in the “La Paz” Hospital clinical trials in this field and also the possibility of transferring new and Autonomous University of Madrid [UAM]), led by Professor Dam- products to the market. ian García Olmo. In 2004 they established a fruitful collaboration with the Spanish biotech company Cellerix, which sponsored the first clini- Declaration of Competing Interest cal trials with the product. In 2011, the Belgian company Tigenix acquired Cellerix, but the cell production remained based in Tres Can- This manuscript has been supported by the Instituto de Salud Car- tos (Madrid). Tigenix further developed the product until its approval los III (ISCIII) through the project “RD16/0011/0001: Red de Terapia in March 2018 by the European Medicines Agency after the outcome Celular”, from the sub-program RETICS, integrated in the “Plan Estatal of the pivotal phase 3 trial ADMIRE-CD [3,14]. Takeda, one of the big- de I+D+I 2013-2016” and co-financed by the European Regional gest pharmaceutical companies, with an increased interest in ATMP Development Fund “A way to make Europe”. D.G.O. has been an Advi- products, will finally commercialize the drug in Europe and other mar- sory Board member of TiGenix SAU, and received consulting fees kets. The model of collaborative work established between the “La from Takeda. He also holds patents 10157355957US and US11/ Paz” University Hospital, UAM, TerCel network research groups and 167061 related to Darvadstrocel. The remaining authors do not Tigenix has been the cornerstone for the development of Darvadstro- declare any conflict of interest regarding this article. cel. This is an example of how networking and collaborative approaches can propel the transfer of ATMPs based on cell products from academic research groups to patients through biotechnology or Author Contributions big pharmaceutical companies. Conception and design, collection and/or assembly of data, manuscript writing: FSG, JMM, DGO, FP, SM, AZ, FFA, JJTA, MT, IF, LB, TerCel and Future Areas for Improvement JLLG, and JGS. All authors have approved the final article. The Tigenix-La Paz-UAM-TerCel strategy has been a story of suc- Acknowledgments cess but additional approaches in the same way with other products need to be promoted. TerCel currently holds 13 patents under exploi- We are grateful to all TerCel research groups whose principal tation (of a total of 63 patents registered by TerCel groups) and more investigators and members are listed at http://www.red-tercel.com/ collaboration with biotechnology companies is needed. In addition, cardiocel.asp, http://www.red-tercel.com/neurocel.asp and http:// the development of large multicenter phase 3 trials within the net- www.red-tercel.com/oshicel.asp. work should be increased. In this regard, in 2017 three TerCel part- ners were included in a European multicenter phase 2b trial in References degenerative disc disease (RESPINE) [15], and in 2018, six phase 2 and 3 multicenter trials have obtained public funding and will be [1] Okada K, Sato Y, Sugiyama D, Sawa Y. Establishment of the National Consortium completed in the next few years. 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Factors of diabetic foot), the AGTPII trial (a phase 2 trial that evaluates the affecting the turnaround time for manufacturing, testing, and release of cell ther- effects of the adipose-derived graft transposition in myocardial post- apy products prepared at multiple sites in support of multicenter cardiovascular ischemic scars), the CaSeC-HF trial (a phase 2 study assessing the regenerative medicine protocols: a Cardiovascular Cell Therapy Research Net- work (CCTRN) study. Transfusion 2012;52(10):2225–33. safety and efficacy of intracoronary allogeneic cardiac stem cells in [5] de Wilde S, Coppens DGM, Hoekman J, de Bruin ML, Leufkens HGM, ischemic chronic heart failure) and a phase 2 trial that explores the Guchelaar HJ, et al. EU decision-making for marketing authorization of role of intramuscular autologous mononuclear cells in amyotrophic advanced therapy medicinal products: a case study. Drug Discov Today 2018;23(7):1328–33. lateral sclerosis. Finally, for the sixth trial (CART19-BE-02), some Ter- [6] TerCel R.Information for patients. http://www.red-tercel.com/presentacion.asp; Cel groups have started to collaborate in new approaches to cover Accesed April 2019. academic immunotherapy trials with CAR technology [16]. This trial [7] Pain E. European debt crisis. Research cuts will cause ‘exodus’ from Spain. Science will explore the role of ARI-001 (an academic CAR-T developed at the 2012;336(6078):139–40. [8] Maciulaitis R, D’Apote L, Buchanan A, Pioppo L, Schneider CK. Clinical develop- Hospital Clinic in Barcelona) in patients with CD19+ relapsed or ment of advanced therapy medicinal products in Europe: evidence that regulators refractory acute lymphoid leukemia. must be proactive. Mol Ther 2012;20(3):479–82. nchez-Guijo et al. / Cytotherapy 22 (2020) 1 5 F. Sa 5 [9] Clinical Trials Database https://www.clinicaltrials.gov/. 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