Effect of Autoimmune Cell Therapy on Immune Cell Content in Patients with COPD: A Randomized Controlled Trial.

OBJECTIVE: To explore the effect of autoimmune cell therapy on immune cells in patients with chronic obstructive pulmonary disease (COPD) and to provide a reference for clinical treatment of COPD. METHODS: Sixty patients with stable COPD were randomly divided into control group and treatment group (n = 30). The control group was given conventional treatment, and the treatment group was given one autoimmune cell therapy on the basis of conventional treatment. The serum levels of CD3+ T cells, CD4+ T cells, CD8+ cells, B cells, and NK cells in the peripheral blood were detected by flow cytometry. Possible adverse reactions were detected at any time during treatment. RESULTS: There were no significant differences in the contents of CD3+ T cells, CD4+ T cells, CD8+ cells, B cells, and NK cells in the serum of the control group (P > 0.05). Compared with before treatment, the contents of CD3+ T cells, CD4+ T cells, CD8+ cells, B cells, and NK cells in the serum of the treatment group were significantly increased (P < 0.05). The ratio of CD4 + /CD8+ T cells in both control and treatment groups did not change significantly during treatment (P > 0.05). There were no significant differences in serum CD3+ T cells, CD4+ T cells, CD8+ cells, B cells, and NK cells in the treatment group at 30 days and 90 days after treatment (P > 0.05), but they were significantly higher than those in the control group (P < 0.05). CONCLUSION: Autoimmune cell therapy can significantly increase the level of immune cells in the body and can be maintained for a long period of time, which has certain clinical benefits for recurrent respiratory tract infections and acute exacerbation in patients with COPD.

Burn Center Organization and Cellular Therapy Integration: Managing Risks and Costs.

The complex management of severe burn victims requires an integrative collaboration of multidisciplinary specialists in order to ensure quality and excellence in healthcare. This multidisciplinary care has quickly led to the integration of cell therapies in clinical care of burn patients. Specific advances in cellular therapy together with medical care have allowed for rapid treatment, shorter residence in hospitals and intensive care units, shorter durations of mechanical ventilation, lower complications and surgery interventions, and decreasing mortality rates. However, naturally fluctuating patient admission rates increase pressure toward optimized resource utilization. Besides, European translational developments of cellular therapies currently face potentially jeopardizing challenges on the policy front. The aim of the present work is to provide key considerations in burn care with focus on architectural and organizational aspects of burn centers, management of cellular therapy products, and guidelines in evolving restrictive regulations relative to standardized cell therapies. Thus, based on our experience, we present herein integrated management of risks and costs for preserving and optimizing clinical care and cellular therapies for patients in dire need.

Recent Developments in Clinical Applications of Mesenchymal Stem Cells in the Treatment of Rheumatoid Arthritis and Osteoarthritis.

Mesenchymal stem cell (MSC) therapies have been used as cell-based treatments for decades, owing to their anti-inflammatory, immunomodulatory, and regenerative properties. With high expectations, many ongoing clinical trials are investigating the safety and efficacy of MSC therapies to treat arthritic diseases. Studies on osteoarthritis (OA) have shown positive clinical outcomes, with improved joint function, pain level, and quality of life. In addition, few clinical MSC trials conducted on rheumatoid arthritis (RA) patients have also displayed some optimistic outlook. The largely positive outcomes in clinical trials without severe side effects establish MSCs as promising tools for arthritis treatment. However, further research is required to investigate its applicability in clinical settings. This review discusses the most recent advances in clinical studies on MSC therapies for OA and RA.

HTA methodology and value frameworks for evaluation and policy making for cell and gene therapies.

This last decade has been marked by significant advances in the development of cell and gene (C&G) therapies, such as gene targeting or stem cell-based therapies. C&G therapies offer transformative benefits to patients but present a challenge to current health technology decision-making systems because they are typically reviewed when clinical efficacy data are very limited and when there is uncertainty about the long-term durability of outcomes. These challenges are not unique to C&G therapies, but they face more of these barriers, reflecting the need for adapting existing value assessment frameworks. Still, C&G therapies have the potential to be cost-effective even at very high price points. The impact on healthcare budgets will depend on the success rate of pipeline assets and on the extent to which C&G therapies will expand to wider pathologies beyond rare or ultra-rare diseases. Getting pricing and reimbursement models right is important for incentivising research and development investment while not jeopardising the sustainability of healthcare systems. Payers and manufacturers therefore need to acknowledge each other's constraints-limitations in the evidence generation on the manufacturer side, budget considerations on the payer side-and embrace innovative thinking and approaches to ensure timely delivery of therapies to patients. Several experts in health technology assessment and clinical experts have worked together to produce this publication and identify methodological and policy options to improve the assessment of C&G therapies, and make it happen better, faster and sustainably in the coming years.

How the COVID-19 pandemic changed cellular therapy at Columbia University Irving Medical Center/NewYork-Presbyterian Hospital.

New York is at the epicenter of the coronavirus disease 2019 (COVID-19) pandemic caused by the SARS-CoV-2 virus. Columbia University Irving Medical Center/NewYork-Presbyterian Hospital (CUIMC/NYPH) had to make changes to its cellular therapy operations to ensure patient, donor, and staff safety and well-being. In this article, we discuss the process changes we instituted for cellular therapy clinical care, collection, processing, and cryopreservation to cope with the rapidly evolving pandemic.

Publication rates and reported results in a cohort of gene- and cell-based therapy trials.

Aim: We investigated publication rates and reported results for gene- and cell-based therapy trials. Materials & methods: In a cohort of Institutional Review Board (IRB)-authorized trials during 2007-2017 in the Netherlands (n = 105), we examine publication rates and reported results in scientific papers and conference abstracts as well as associations with the occurrence of trial characteristics. Results: The publication rate for scientific papers was 27% and 17% for conference abstracts (median survival time: 1050 days). Academic hospitals published more in scientific papers whereas private sponsors published more in conference abstracts. Manufacturing protocols were underreported compared with clinical outcomes. Most publications reported positive results (78%). Conclusion: Publication rates are currently suboptimal indicating a need for enhanced knowledge sharing to stimulate gene- and cell-based therapy development.

Cell and gene therapy manufacturing capabilities in Australia and New Zealand.

Cell and gene therapy products are rapidly being integrated into mainstream medicine. Developing global capability will facilitate broad access to these novel therapeutics. An initial step toward achieving this goal is to understand cell and gene therapy manufacturing capability in each region. We conducted an academic survey in 2018 to assess cell and gene therapy manufacturing capacity in Australia and New Zealand. We examined the following: the number and types of cell therapy manufacturing facilities; the number of projects, parallel processes and clinical trials; the types of products; and the manufacturing and quality staffing levels. It was found that Australia and New Zealand provide diverse facilities for cell therapy manufacturing, infrastructure and capability. Further investment and development will enable both countries to make important decisions to meet the growing need for cell and gene therapy and regenerative medicine in the region.

A multiscale simulation framework for the manufacturing facility and supply chain of autologous cell therapies.

BACKGROUND AIMS: Autologous cell therapy (AuCT) is an emerging therapeutic treatment that is undergoing transformation from laboratory- to industry-scale manufacturing with recent regulatory approvals. Various challenges facing the complex AuCT manufacturing and supply chain process hinder the scale out and broader application of this highly potent treatment. METHODS: We present a multiscale logistics simulation framework, AuCT-Sim, that integrates novel supply chain system modeling algorithms, methods, and tools. AuCT-Sim includes a single facility model and a system-wide network model. Unique challenges of the AuCT industry are analyzed and addressed in AuCT-Sim. Decision-supporting tools can be developed based on this framework to explore "what-if" manufacturing and supply chain scenarios of importance to various cell therapy stakeholder groups. RESULTS: Two case studies demonstrate the decision-supporting capability of AuCT-Sim where one investigates the optimal reagent base stocking level, and the other one simulates a reagent supply disruption event. These case studies serve as guidelines for designing computational experiments with AuCT-Sim to solve specific problems in AuCT manufacturing and supply chain. DISCUSSION: This simulation framework will be useful in understanding the impact of possible manufacturing and supply chain strategies, policies, regulations, and standards informing strategies to increase patient access to AuCT.

Marco legal europeo y español para el desarrollo de las terapias avanzadas y herramientas regulatorias y legales impulsadas a nivel internacional para facilitar el acceso de los pacientes / European and Spanish legal framework for the development of advanced therapies and regulatory and legal tools promoted at international level to facilitate patient access

El marco regulatorio de los medicamentos de terapias avanzadas (terapia celular somática, terapia génica, ingeniería de tejidos y combinados con productos sanitarios) se caracteriza por su singularidad debido a la complejidad en el desarrollo de estos medicamentos poniéndose de manifiesto en el escaso número que han alcanzado una autorización de comercialización. En Europa, al igual que en múltiples países de otros continentes, se han puesto en marcha diferentes medidas regulatorias y legales para intentar facilitar el acceso de los pacientes a estas terapias cuya principal barrera, más allá de la dificultad logística que conllevan, se encuentra en los elevados precios que alcanzan en el mercado

The legal framework of Advanced Therapy Medicinal Products (somatic cell therapy, gene therapy, tissue engineering and combined products with medical devices) is singular due to the complexity of the development of these products resulting in few medicines granted marketing authorization. In Europe, as well as in other countries from different continents, several legal and regulatory measures have been put in place to facilitate patients' accessibility to these medicinal products. Beyond the logistic challenge that ATMPs pose, the high price of marketed products represents a major barrier for accessibility

Isolation and Characterization of Human Myoblast Culture In Vitro for Technologies of Cell and Gene Therapy of Skeletal Muscle Pathologies.

We analyzed cultures of 5 independent myoblast lines from human skeletal muscles. It was shown that the content of desmin-positive cells in cultures at early passages exceeds 90%. Typical morphofunctional signs of myogenic differentiation disturbances were identified and their dynamics was studied. Signs of alternative adipogenic and chondrogenic differentiation of cells were revealed. Based on these data, limitations for the use of myoblast cultures of certain passages for biomedical research and cell therapy were evaluated.

The survey on cellular and tissue-engineered therapies in Europe and neighboring Eurasian countries in 2014 and 2015.

BACKGROUND AIMS: With the support of five established scientific organizations, this report, the seventh of its kind, describes activity in Europe for the years 2014 and 2015 in the area of cellular and tissue-engineered therapies, excluding hematopoietic stem cell (HSC) treatments for the reconstitution of hematopoiesis. METHODS: In 2015 [respectively 2014], 205 [276] teams from 32 countries responded to the cellular and tissue-engineered therapy survey; 178 [126] teams reported treating 3686 [2665] patients. RESULTS: Indications were musculoskeletal/rheumatological disorders (32% [33%]), cardiovascular disorders (12% [21%]), hematology/oncology (predominantly prevention or treatment of graft versus host disease and HSC graft enhancement; 20% [20%]), neurological disorders (4% [6%]), gastrointestinal disorders (<1% [1%]) and other indications (31% [20%]). The majority of autologous cells (60% [73%]) were used to treat musculoskeletal/rheumatological (44% [36%]) disorders, whereas allogeneic cells were used mainly for hematology/oncology (61% [68%]). The reported cell types were mesenchymal stromal cells (40% [49%]), chondrocytes (13% [6%]), hematopoietic stem cells (12% [23%]), dermal fibroblasts (8% [3%]), dendritic cells (2% [2%]), keratinocytes (1% [2%]) and others (24% [15%]). Cells were expanded in vitro in 63% [40%] of the treatments, sorted in 16% [6%] of the cases and rarely transduced (<1%). Cells were delivered predominantly as suspension 43% [51%], intravenously or intra-arterially (30% [30%]), or using a membrane/scaffold (25% [19%]). DISCUSSION: The data are compared with those from previous years to identify trends in a still unpredictably evolving field. Perspectives of representatives from plastic surgery practitioners, Iran and ISCT are presented (contributing authors D.A. Barbara, B. Hossein and W.L. Mark, respectively).

The acceptability of stem cell-based fertility treatments for different indications.

STUDY QUESTION: What is the acceptability of using stem cell-based fertility treatments (SCFT) for different indications according to gynaecologists and the general public? SUMMARY ANSWER: The majority of gynaecologists and the general public accept SCFT for the indications female or male infertility in young heterosexual couples, and female infertility in single women and same-sex couples. WHAT IS KNOWN ALREADY: SCFT could result in genetic parenthood for intended parents with indications that cannot be treated using currently available methods, such as being in a same-sex relationship or female post-menopausal age. It is unclear whether the acceptability of SCFT differs between indications for treatment and whether gynaecologists and the general public differ in their assessments. STUDY DESIGN SIZE, DURATION: In November 2015, a cross-sectional survey was disseminated among 179 gynaecologists and a panel of 1250 respondents comprising a representative sample of the Dutch general public. PARTICIPANTS/MATERIALS, SETTING, METHODS: The potential indications for future SCFT to achieve genetic parenthood were identified by literature review. A questionnaire was developed, reviewed by experts from different disciplines and tested among the general public. The questionnaire asked whether treating eight groups of intended parents with SCFT was acceptable or not. Regression analysis examined whether demographic characteristics influenced choices and whether the general public and gynaecologists differed in opinion. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 82 (46%) gynaecologists and 772 (62%) members of the general public completed the survey. The acceptability of using SCFT varied according to both gynaecologists and the general public between the eight groups of intended parents (P < 0.001). The majority of the Dutch general public accepts SCFT for six out of eight possible indications, namely female infertility in young heterosexual couples (94%), male infertility in young heterosexual couples (94%), unexplained infertility in young heterosexual couples (83%), female infertility in single women (69%), lesbian couples (68%) and gay couples (62%). The majority of gynaecologists also found treating these groups acceptable, except for the indication of unexplained infertility, which was only accepted by a minority of gynaecologists (43%). A minority of both the general public and gynaecologists accepted SCFT for fertile women who want a child that is genetically only her own (27 and 6%, respectively) and for female infertility in heterosexual couples in which the woman is over 50 years of age (17% and 26%, respectively). Attaching low importance to religion, having progressive political preferences, not having a university degree, having experienced infertility, being a woman, being older and not being of European ethnicity were positively associated with considering using SCFT acceptable for one or multiple indications. LARGE SCALE DATA: N/A. LIMITATIONS REASONS FOR CAUTION: The generalizability of our findings to future decades or other countries might be limited as opinions about novel technologies change over time and might vary across cultures. Support among gynaecologists and the general public is interesting but not proof of ethical acceptability. WIDER IMPLICATIONS OF THE FINDINGS: Once proven safe and effective, fear of limited acceptability by the general public is unwarranted, and thus should not stop gynaecologists from offering SCFT to single infertile women and same-sex couples in addition to young infertile heterosexual couples. STUDY FUNDING AND COMPETING INTEREST(S): Funded by the Young Academy of the Royal Netherlands Academy of Arts and Sciences and the Universities of Amsterdam and Leuven. No conflict of interest to declare.

Understanding clinical development of chimeric antigen receptor T cell therapies.

BACKGROUND AIMS: In the past decade, many clinical trials with gene- and cell-based therapies (GCTs) have been performed. Increased interest in the development of these drug products by various stakeholders has become apparent. Despite this growth in clinical studies, the number of therapies receiving marketing authorization approval (MAA) is lagging behind. To enhance the success rate of GCT development, it is essential to better understand the clinical development of these products. Chimeric antigen receptor (CAR) T cells are a GCT product subtype with promising efficacy in cancer treatment which are tested in many clinical trials, but have not yet received MAA. METHODS: We generated an overview of the characteristics of CAR T-cell clinical development in the United States, Canada and Europe. Subsequently, the characteristics of clinical trials with CAR T-cell products that proceeded to a subsequent clinical trial, used as a proxy for success, were compared with those that did not proceed. RESULT: From the U.S. and European Union clinical trial databases, 106 CAR T-cell trials were selected, from which 49 were linked to a subsequent trial and 57 were not. The majority of the trials had an academic sponsor from which most did not proceed, whereas most commercially sponsored trials were followed by another clinical trial. Furthermore, trials with a subsequent trial more frequently recruited large patient cohorts and were more often multicenter compared with trials that were not followed up. DISCUSSION: These characteristics can be used by investigators to better design clinical trials with CAR T cells. We encourage sponsors to plan clinical development ahead for a higher efficiency of product development and thereby achieving a higher success rate of development towards MAA.

Cell Therapy Regulation in Taiwan.

Cell therapy is not only a novel medical practice but also a medicinal product [cell therapy product (CTP)]. More and more CTPs are being approved for marketing globally because of the rapid development of biomedicine in cell culture, preservation, and preparation. However, regulation is the most important criterion for the development of CTPs. Regulations must be flexible to expedite the process of marketing for new CTPs. Recently, the Taiwan Food and Drug Administration (TFDA) updated the related regulations such as regulation of development, current regulatory framework and process, and the application and evaluation processes. When the quality of CTPs has been improved significantly, their safety and efficacy are further ensured. The treatment protocol, a new design for adaptive licensing to current clinical practice, is a rapid process for patients with life-threatening diseases or serious conditions for which there are no suitable drugs, medical devices, or other therapeutic methods available. The hospital can submit the treatment protocol to apply for cell therapy as a medical practice, which may result in easier and faster cell therapy development, and personalized treatment for individual patients will evolve quickly.

Hospital Exemption for Advanced Therapy Medicinal Products: Issue in Application in the European Union Member States.

Regulation (EC) 1394/2007 of the European Parliament and the Council on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004 allowed the use of non - authorized advanced therapy medicinal products under the certain circumstances. This socalled hospital exemption rule needs to be applied in the each Member State of the European Union individually and for this purpose Member States should provide national procedures and control measures. The aim of this article is to clear up the criteria for hospital exemption listed in Regulation (EC) 1394/2007 and to contrast the difference in implementing hospital exemption rule into national legal regimes on examples of the United Kingdom, Lithuania and Poland.