How Can Accreditation Bodies, Such as JACIE or FACT, Support Centres in Getting Qualified?

AbstractThe FACT-JACIE accreditation system is based on a standard-driven process covering all the steps of HSC transplant activity, from donor selection to clinical care. Since the first approval of the First Edition of the Standards in 1998, over 360 HSCT programmes or facilities have been accredited at least once, most of them achieving subsequent re-accreditations (Snowden et al. 2017). The positive impact of the accreditation process in the EBMT Registry has been well established (Gratwohl et al. 2014). Starting with version 6.1, the standards include new items specifically developed for other cellular therapy products, with special reference to immune effector cells (IECs). This reflects the rapid evolution of the field of cellular therapy, primarily (but not exclusively) through the use of genetically modified cells, such as CAR-T cells. FACT-JACIE standards cover a wide range of important aspects that can be of use for centres that aim to be accredited in their countries to provide IEC therapy. Notably, FACT-JACIE accreditation itself is a key (or even a prerequisite) condition in some countries for approval by health authorities to provide commercial CAR-T cell therapy and is also valued by pharmaceutical companies (both those developing clinical trials and those manufacturing commercial products), which also inspect the cell therapy programmes and facilities established at each centre (Yakoub-Agha et al. 2020). Interest in applying for FACT-JACIE accreditation that includes IEC therapeutic programmes is clearly increasing, from four applications in 2017 to 36 applications approved in 2019. The standards do not cover the manufacturing of such cells but include the chain of responsibilities when the product is provided by a third party (Maus and Nikiforow 2017). In any case, all the steps in the process in which the centre is involved (e.g., patient or donor evaluations, cell collection, cell reception, and storage) are covered by the standards, including the appropriate agreements with the internal partners, including the pharmacy department. In addition, from a clinical perspective, IECs may require special safety monitoring systems due to the high frequency of acute adverse events related to the massive immunological reaction against the tumour. Although examples and explanations are found in the standard manual, here, the special importance of identifying and managing cytokine release syndrome (CRS) should be emphasized, and the standards focus not on specific therapeutic algorithms but on ensuring that medical and nursing teams are sufficiently trained in the early detection of this and other potential complications (e.g., neurological complications). They also pay attention to the full-time availability within the institution and its pharmacy of the necessary medication to address complications and the capacitation and involvement of Intensive Care and Neurology Department professionals to provide urgent care if needed. Forthcoming cellular therapy products, currently under investigation, will show a wider range of risk profiles, therefore requiring product-specific risk assessment and consequent adaptation of the clinical procedures for different classes of products. The FACT-JACIE standards will continue to adapt to these future needs to assist centres in their achievement of optimal clinical outcomes

Cell and gene therapy workforce development: the role of the International Society for Cell & Gene Therapy (ISCT) in the creation of a sustainable and skilled workforce in Europe

Advanced therapy medicinal products; Career development; TrainingMedicamentos de terapia avanzada; Desarrollo profesional; FormaciónMedicaments de teràpia avançada; Desenvolupament professional; FormacióThe development and production of cell gene and tissue (CGT)-based therapies requires a specialized workforce. Entering the CGT arena is complex because it involves different scientific and biomedical aspects (e.g., immunology, stem cell biology and transplantation), as well as knowledge of regulatory affairs and compliance with pharmaceutical quality standards. Currently, both industry and academia are facing a worldwide workforce shortage, whereas only a handful of educational and training initiatives specifically address the peculiarities of CGT product development, the procurement of substances of human origin, the manufacturing process itself and clinical monitoring and biovigilance. The training offered by traditional Master's and PhD programs is not suited for training a skilled workforce ready to enter the increasingly fast-growing CGT field. Indeed, typically these programs are of long duration and only partially cover the required competencies, whereas the demand for a specialized workforce relentlessly increases. In this paper, we (i) present and discuss our understanding of the roots of current growth acceleration of the CGT field; (ii) anticipate future workforce needs due to the expected increase of marketed CGT-based therapies and (iii) evaluate potential solutions that seek to adapt, develop and implement current educational and training initiatives. Importantly for these solutions, we call for scientific societies, such as the International Society for Cell & Gene Therapy, to play a more active role and act as catalysers for new initiatives, building bridges between academia and Industry to establish effective educational and training programs that will engage and prepare a new generation of qualified professionals for entry into the CGT field

Bone Marrow Mesenchymal Stem Cells for Improving Hematopoietic Function: An In Vitro and In Vivo Model. Part 2: Effect on Bone Marrow Microenvironment

The aim of the present study was to determine how mesenchymal stem cells (MSC) could improve bone marrow (BM) stroma function after damage, both in vitro and in vivo. Human MSC from 20 healthy donors were isolated and expanded. Mobilized selected CD34+ progenitor cells were obtained from 20 HSCT donors. For in vitro study, long-term bone marrow cultures (LTBMC) were performed using a etoposide damaged stromal model to test MSC effect in stromal confluence, capability of MSC to lodge in stromal layer as well as some molecules (SDF1, osteopontin,) involved in hematopoietic niche maintenance were analyzed. For the in vivo model, 64 NOD/SCID recipients were transplanted with CD34+ cells administered either by intravenous (IV) or intrabone (IB) route, with or without BM derived MSC. MSC lodgement within the BM niche was assessed by FISH analysis and the expression of SDF1 and osteopontin by immunohistochemistry. In vivo study showed that when the stromal damage was severe, TP-MSC could lodge in the etoposide-treated BM stroma, as shown by FISH analysis. Osteopontin and SDF1 were differently expressed in damaged stroma and their expression restored after TP-MSC addition. Human in vivo MSC lodgement was observed within BM niche by FISH, but MSC only were detected and not in the contralateral femurs. Human MSC were located around blood vessels in the subendoestal region of femurs and expressed SDF1 and osteopontin. In summary, our data show that MSC can restore BM stromal function and also engraft when a higher stromal damage was done. Interestingly, MSC were detected locally where they were administered but not in the contralateral femur

Dasatinib as a Bone-Modifying Agent: Anabolic and Anti-Resorptive Effects

This is an open-access article distributed under the terms of the Creative Commons Attribution License.-- et al.[Background]: Bone loss, in malignant or non-malignant diseases, is caused by increased osteoclast resorption and/or reduced osteoblast bone formation, and is commonly associated with skeletal complications. Thus, there is a need to identify new agents capable of influencing bone remodeling. We aimed to further pre-clinically evaluate the effects of dasatinib (BMS-354825), a multitargeted tyrosine kinase inhibitor, on osteoblast and osteoclast differentiation and function. [Methods]: For studies on osteoblasts, primary human bone marrow mensenchymal stem cells (hMSCs) together with the hMSC-TERT and the MG-63 cell lines were employed. Osteoclasts were generated from peripheral blood mononuclear cells (PBMC) of healthy volunteers. Skeletally-immature CD1 mice were used in the in vivo model. [Results]: Dasatinib inhibited the platelet derived growth factor receptor-β (PDGFR-β), c-Src and c-Kit phosphorylation in hMSC-TERT and MG-63 cell lines, which was associated with decreased cell proliferation and activation of canonical Wnt signaling. Treatment of MSCs from healthy donors, but also from multiple myeloma patients with low doses of dasatinib (2-5 nM), promoted its osteogenic differentiation and matrix mineralization. The bone anabolic effect of dasatinib was also observed in vivo by targeting endogenous osteoprogenitors, as assessed by elevated serum levels of bone formation markers, and increased trabecular microarchitecture and number of osteoblast-like cells. By in vitro exposure of hemopoietic progenitors to a similar range of dasatinib concentrations (1-2 nM), novel biological sequelae relative to inhibition of osteoclast formation and resorptive function were identified, including F-actin ring disruption, reduced levels of c-Fos and of nuclear factor of activated T cells 1 (NFATc1) in the nucleus, together with lowered cathepsin K, αVβ3 integrin and CCR1 expression. [Conclusions]: Low dasatinib concentrations show convergent bone anabolic and reduced bone resorption effects, which suggests its potential use for the treatment of bone diseases such as osteoporosis, osteolytic bone metastasis and myeloma bone disease. © 2012 Garcia-Gomez et al.This work was supported by grants from the Spanish Ministry of Science and Innovation – ISCIII (PI081825); Mutua Madrileña Medical Research Foundation (AP27262008); Centro en Red of Regenerative Medicine and Cellular Therapy from Castilla y León, Consejería de Sanidad JCyL – ISCIII; the Cooperative Research Thematic Network in Cancer (RTICC; RD06/0020/0006 and RD03/0020/0041); and Spanish FIS (PS09/01897). AG-G and CS are supported by the Centro en Red of Regenerative Medicine and Cellular Therapy from Castilla y León Project.Peer Reviewe

Cell and gene therapy workforce development : the role of the International Society for Cell & Gene Therapy (ISCT) in the creation of a sustainable and skilled workforce in Europe

Altres ajuts: acords transformatius de la UABThe development and production of cell gene and tissue (CGT)-based therapies requires a specialized workforce. Entering the CGT arena is complex because it involves different scientific and biomedical aspects (e.g., immunology, stem cell biology and transplantation), as well as knowledge of regulatory affairs and compliance with pharmaceutical quality standards. Currently, both industry and academia are facing a worldwide workforce shortage, whereas only a handful of educational and training initiatives specifically address the peculiarities of CGT product development, the procurement of substances of human origin, the manufacturing process itself and clinical monitoring and biovigilance. The training offered by traditional Master's and PhD programs is not suited for training a skilled workforce ready to enter the increasingly fast-growing CGT field. Indeed, typically these programs are of long duration and only partially cover the required competencies, whereas the demand for a specialized workforce relentlessly increases. In this paper, we (i) present and discuss our understanding of the roots of current growth acceleration of the CGT field; (ii) anticipate future workforce needs due to the expected increase of marketed CGT-based therapies and (iii) evaluate potential solutions that seek to adapt, develop and implement current educational and training initiatives. Importantly for these solutions, we call for scientific societies, such as the International Society for Cell & Gene Therapy, to play a more active role and act as catalysers for new initiatives, building bridges between academia and Industry to establish effective educational and training programs that will engage and prepare a new generation of qualified professionals for entry into the CGT field

Data from: Insights into the human mesenchymal stromal/stem cell identity through integrative transcriptomic profiling

Background: Mesenchymal Stromal/Stem Cells (MSCs), isolated under the criteria established by the ISCT, still have a poorly characterized phenotype that is difficult to distinguish from similar cell populations. Although the field of transcriptomics and functional genomics has quickly grown in the last decade, a deep comparative analysis of human MSCs expression profiles in a meaningful cellular context has not been yet performed. There is also a need to find a well-defined MSCs gene-signature because many recent biomedical studies show that key cellular interaction processes (i.e. inmuno-modulation, cellular cross-talk, cellular maintenance, differentiation, epithelial-mesenchymal transition) are dependent on the mesenchymal stem cells within the stromal niche. Results: In this work we define a core mesenchymal lineage signature of 489 genes based on a deep comparative analysis of multiple transcriptomic expression data series that comprise: (i) MSCs of different tissue origins; (ii) MSCs in different states of commitment; (iii) other related non-mesenchymal human cell types. The work integrates several public datasets, as well as de-novo produced microarray and RNA-Seq datasets. The results present tissue-specific signatures for adipose tissue, chorionic placenta, and bone marrow MSCs, as well as for dermal fibroblasts; providing a better definition of the relationship between fibroblasts and MSCs. Finally, novel CD marker patterns and cytokine-receptor profiles are unravelled, especially for BM-MSCs; with MCAM (CD146) revealed as a prevalent marker in this subtype of MSCs. Conclusions: The improved biomolecular characterization and the released genome-wide expression signatures of human MSCs provide a comprehensive new resource that can drive further functional studies and redesigned cell therapy applications

Data from: Insights into the human mesenchymal stromal/stem cell identity through integrative transcriptomic profiling

Background: Mesenchymal Stromal/Stem Cells (MSCs), isolated under the criteria established by the ISCT, still have a poorly characterized phenotype that is difficult to distinguish from similar cell populations. Although the field of transcriptomics and functional genomics has quickly grown in the last decade, a deep comparative analysis of human MSCs expression profiles in a meaningful cellular context has not been yet performed. There is also a need to find a well-defined MSCs gene-signature because many recent biomedical studies show that key cellular interaction processes (i.e. inmuno-modulation, cellular cross-talk, cellular maintenance, differentiation, epithelial-mesenchymal transition) are dependent on the mesenchymal stem cells within the stromal niche. Results: In this work we define a core mesenchymal lineage signature of 489 genes based on a deep comparative analysis of multiple transcriptomic expression data series that comprise: (i) MSCs of different tissue origins; (ii) MSCs in different states of commitment; (iii) other related non-mesenchymal human cell types. The work integrates several public datasets, as well as de-novo produced microarray and RNA-Seq datasets. The results present tissue-specific signatures for adipose tissue, chorionic placenta, and bone marrow MSCs, as well as for dermal fibroblasts; providing a better definition of the relationship between fibroblasts and MSCs. Finally, novel CD marker patterns and cytokine-receptor profiles are unravelled, especially for BM-MSCs; with MCAM (CD146) revealed as a prevalent marker in this subtype of MSCs. Conclusions: The improved biomolecular characterization and the released genome-wide expression signatures of human MSCs provide a comprehensive new resource that can drive further functional studies and redesigned cell therapy applications