Somatic Cell Therapy Research Articles

ESOT Roadmap for Advanced Therapy Medicinal Products in Transplantation: Navigating Regulatory Challenges to Enhance Access and Care.

The field of organ transplantation is experiencing a transformative shift with the rise of Advanced Therapy Medicinal Products (ATMPs), which include gene therapies, somatic cell therapies, and tissue-engineered products. These therapies offer new, potentially curative treatments for longstanding medical challenges, impacting numerous patients. However, their adoption is hindered by complex regulatory frameworks, high production costs, and inconsistent access across Europe. The ESOT ATMP Task Force's position paper analyzes these challenges from research to clinical application, advocating for a coordinated strategy to position Europe as a leader in ATMP development. It proposes specific actions such as streamlining regulatory pathways to accelerate approvals, boosting funding for ATMP research, and creating specialized facilities for development and implementation. The paper also highlights the critical roles of patient engagement and real-world evidence in optimizing clinical and regulatory practices.

Are genetically modified protozoa eligible for ATMP status? Concerning the legal categorization of an oncolytic protozoan drug candidate.

Neospora caninum is an obligate intracellular protozoan that affects several animal species. It is not pathogenic for humans, and its ability to infect and lyse a variety of cells and stimulate the immune system makes it an interesting drug candidate in oncology. The intrinsic oncolytic properties of N. caninum have been confirmed in several preclinical models. Moreover, it can be modified to improve its safety and/or efficacy against cancer cells. In this study, we propose the legal categorization of this new biological drug candidate and the impact of modifications, notably the integration of a suicide gene, the deletion of a gene allowing its multiplication in healthy cells, and/or the insertion of a gene coding for a therapeutic protein into its genome. When unmodified, N. caninum can be categorized as a biological medicinal product, whereas modifications aimed at increasing its safety classify it as a Somatic Cell Therapy Medicinal Product, and modifications aiming to increase its efficacy or both safety and efficacy make it as a Gene Therapy Medicinal Product. This categorization is fundamental because it determines the guidelines applicable for preclinical development. These guidelines being numerous and complex, we have focused on the key requirements necessary for the development of the future medicinal product.

Challenges and Emerging Strategies in ATMPs

Advanced therapy medicinal products (ATMPs) are a significant innovation in medicine, categorized by the European Medicines Agency into four types: gene therapy medicines, somatic cell therapy medicines, tissue-engineered medicines and combined ATMPs. They hold potential for treating various conditions, including rare diseases, degenerative diseases like Parkinson’s and Alzheimer’s and cancers. The global market for ATMPs was valued at US$9.28 billion in 2023 and is projected to reach US$22.80 billion by 2032, growing at a compound annual growth rate of 10.50%. Gene and cell therapies are advancing rapidly, with over 1,700 approved clinical trials worldwide. Notable successes include Glybera for lipoprotein lipase deficiency and Roctavian for haemophilia. Despite limited current approvals, many gene therapies are expected to gain market approval soon. Challenges include stringent regulatory requirements, safety and ethical concerns. For example, Glybera faced multiple rejections before approval due to safety issues. Current clinical studies are exploring immune-based therapies like CAR-T, cytotoxic T lymphocytes, natural killer cells and mesenchymal stromal cells. CAR-T cell therapies, such as Yescarta and Kymriah, have shown promise in treating B-cell lymphoma. However, high development and manufacturing costs limit accessibility, exemplified by Hemgenix, a gene therapy for haemophilia B priced at US$3.5 million. Increased ATMP sales have spurred investor interest in R&D, leading to advancements in technology and manufacturing processes. Despite challenges, the future is promising with more academic and commercial ATMP clinical trials. There are now 32 approved gene therapies globally. To attract industries, the focus should shift from rare to common diseases, and alternative reimbursement models could help manage high costs. A trained workforce and public involvement are crucial for the successful delivery of ATMPs.

CO113 Impact of Clinical Pharmacist-Led Intervention on Somatic Cell Therapy Medicinal Product Circuit in Portugal

CO113 Impact of Clinical Pharmacist-Led Intervention on Somatic Cell Therapy Medicinal Product Circuit in Portugal

Cell-based medicinal products approved in the European Union: current evidence and perspectives.

Advanced Therapy Medicinal Products (ATMPs) are innovative clinical treatments exploiting the pharmacological, immunological, or metabolic properties of cells and/or gene(s) with the aim to restore, correct, or modify a biological function in the recipient. ATMPs are heterogeneous medicinal products, developed mainly as individualized and patient-specific treatments, and represent new opportunities for diseases characterized by a high-unmet medical need, including rare, genetic and neurodegenerative disorders, haematological malignancies, cancer, autoimmune, inflammatory and orthopaedic conditions. Into the European Union (EU) market, the first ATMP has been launched in 2009 and, to date, a total of 24 ATMPs have been approved. This review aims at reporting on current evidence of cell-based therapies authorized in the EU, including Somatic Cell Therapies, Tissue Engineering Products, and Cell-based Gene Therapy Products as Chimeric Antigen Receptor (CAR) T-cells, focusing on the evaluation of efficacy and safety in clinical trials and real-world settings. Despite cell-based therapy representing a substantial promise for patients with very limited treatment options, some limitations for its widespread use in the clinical setting remain, including restricted indications, highly complex manufacturing processes, elevated production costs, the lability of cellular products over time, and the potential safety concerns related to the intrinsic characteristics of living cells, including the risk of severe or life-threatening toxicities, such as CAR-T induced neurotoxicity and cytokine release syndrome (CRS). Although encouraging findings support the clinical use of ATMPs, additional data, comparative studies with a long-term follow-up, and wider real-world evidences are needed to provide further insights into their efficacy and safety profiles.

Preclinical Validation of an Advanced Therapy Medicinal Product Based on Cytotoxic T Lymphocytes Specific for Mutated Nucleophosmin (NPM1mut) for the Treatment of NPM1mut-Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) with nucleophosmin (NPM1) genetic mutations is the most common subtype in adult patients. Refractory or relapsed disease in unfit patients or after allogeneic hematopoietic stem cell transplantation (allo-HSCT) has a poor prognosis. NPM1-mutated protein, stably expressed on tumor cells but not on normal tissues, may serve as an ideal target for NPM1-mutated AML immunotherapy. The study aim was to investigate the feasibility of producing mutated-NPM1-specific cytotoxic T cells (CTLs) suitable for somatic cell therapy to prevent or treat hematologic relapse in patients with NPM1-mutated AML. T cells were expanded or primed from patient or donor peripheral blood mononuclear cells by NPM1-mutated protein-derived peptides, and tested for leukemia antigen-targeted cytotoxic activity, cytokine production and hematopoietic precursor inhibitory effect. We found that mutated-NPM1-specific CTLs, displaying specific cytokine production and high-level cytotoxicity against patients' leukemia blasts, and limited inhibitory activity in clonogenic assays, could be obtained from both patients and donors. The polyfunctional mutated-NPM1-specific CTLs included both CD8+ and CD4+ T cells endowed with strong lytic capacity. Our results suggest that mutated-NPM1-targeted CTLs may be a useful therapeutic option to control low-tumor burden relapse following conventional chemotherapy in older NPM1-mutated AML patients or eradicate persistent MRD after HSCT.

A pipeline analysis of advanced therapy medicinal products

Advanced therapy medicinal products (ATMPs) are innovative biological products categorised as either gene, somatic cell, tissue-engineered or combined therapies. As of March 2022, 12 ATMPs are marketed in the EU and UK. We identified 482 unique ATMPs within 616 technology records from the National Institute for Health and Care Research Innovation Observatory database, four of which are currently marketed. These 482 ATMPs were identified in 583 clinical trials. Of the 616 records, 57.1% were for gene therapies and 1.6% were for combined therapies. Records covered various indications, including 130 haematological malignancies and 60 genetic disorders. Marketing authorisation intelligence was included in 14% of records.

Clinical Trials on Advanced Therapy Investigational Medicinal Products in Spain (2004-2022): Experience and Challenges for the Future.

Clinical investigation is the basis for establishing how useful advanced therapy investigational medicinal products (ATiMP) are for the treatment of serious diseases.In Spain, clinical trials (CT) on ATiMP need to follow the general European legislation on CT with medicinal products plus some specific legislation and guidance depending on the type of ATiMP.This chapter describes the characteristics of CT on ATiMP authorized in Spain in the period 2004-2022 and the legislation applicable along this period. There are clear differences in the clinical trials conducted by non commercial and commercial sponsors: the first have been more involved in CT on somatic cell therapy medicinal products (sCTMP) and tissue-engineered products (TEP), while the second drive more the CT on gene therapy medicinal products (GTMP) in the last years. Difficulties of budget and resources especially by non-commercial sponsors to meet the regulatory requirements are highlighted. The importance of complying with transparency rules with respect to CT on ATiMP is also discussed.

Treatment of Inherited Retinal Dystrophies with Somatic Cell Therapy Medicinal Product: A Review.

Inherited retinal dystrophies and retinal degenerations related to more common diseases (i.e., age-related macular dystrophy) are a major issue and one of the main causes of low vision in pediatric and elderly age groups. Advancement and understanding in molecular biology and the possibilities raised by gene-editing techniques opened a new era for clinicians and patients due to feasible possibilities of treating disabling diseases and the reduction in their complications burden. The scope of this review is to focus on the state-of-the-art in somatic cell therapy medicinal products as the basis of new insights and possibilities to use this approach to treat rare eye diseases.

Dental-Pulp Stem Cells as a Therapeutic Strategy for Ischemic Stroke.

Regenerative medicine aims to restore human functions by regenerating organs and tissues using stem cells or living tissues for the treatment of organ and tissue defects or dysfunction. Clinical trials investigating the treatment of cerebral infarction using mesenchymal stem cells, a type of somatic stem cell therapy, are underway. The development and production of regenerative medicines using somatic stem cells is expected to contribute to the treatment of cerebral infarction, a central nervous system disease for which there is no effective treatment. Numerous experimental studies have shown that cellular therapy, including the use of human dental pulp stem cells, is an attractive strategy for patients with ischemic brain injury. This review describes the basic research, therapeutic mechanism, clinical trials, and future prospects for dental pulp stem cell therapy, which is being investigated in Japan in first-in-human clinical trials for the treatment of patients with acute cerebral ischemia.

POSA265 HTA Requirements for Advanced Therapy Medicinal Products (ATMPS) in Germany

ATMPs are medicines for human use that can be classified into gene therapy, somatic-cell therapy and tissue-engineered medicines. If these are medicines with new active substances, ATMPs have to undergo a benefit assessment according to §35a Social Code Book (SGB) V. The objective of this analysis was to determine if ATMPs have the same Health Technology Assessment (HTA) requirements as other drugs in Germany.

Help us develop an e-learning module on cell and gene therapies

Cell and gene therapies are emerging types of medicines that aim to provide treatment opportunities to individuals, with application across a number of illnesses. Cell and gene therapies are types of advanced therapy medicinal products (ATMPs) that are biological medicines based on either genes, cells or tissues. Somatic cell therapies refer to medicinal products that […]

Advanced therapy medicinal products: Regulatory framework, hospital and pharmaceutical circuits in Europe and France

Advanced therapy medicinal products (ATMPs) represent a new class of biological medicines. The European regulation has classified ATMPs into three categories: gene therapy medicinal products, somatic cell therapy medicinal products, and Tissue-Engineered products. If one of these categories incorporates a medical device, the medicine is defined as a Combined ATMP. The specificity and complexity of these innovative drugs have required a complete reorganization of hospital and pharmaceutical circuits, from patient eligibility to drug administration. Indeed, increased interaction and collaboration between different healthcare professionals are essential in order to guarantee quality and safety of these innovative medicines.

Evaluation of Advanced Therapy Medicinal Products by the National Institute for Health and Care Excellence (NICE): An Updated Review

This review discusses the methodological challenges to the evaluation of advanced therapy medicinal products (ATMPs) by the UK National Institute for Health and Care Excellence (NICE). We analysed the health technology appraisals (both published and in development) of ATMPs conducted by NICE in England until July 2021. A total of 14 health technology appraisals of ATMPs were included, of which two were in development and 12 had been published. There were ten gene therapy products (talimogene laherparepvec [TA410], strimvelis [HST7], tisagenlecleucel [TA554 and TA567], axicabtagene ciloleucel [TA559], voretigene neparvovec [HST11], autologous anti-CD19-transduced CD3+ cells [TA677], betibeglogene autotemcel [ID968], onasemnogene abeparvovec [HST15] and OTL-200 [ID1666]), one tissue engineered product (holoclar [TA467]) and three somatic cell therapy products (darvadstrocel [TA556] and autologous chondrocyte implantation [ACI] [TA477 and TA508]). Only three of these technologies were not recommended by NICE, although four were only recommended within the Cancer Drugs Fund. There was large uncertainty in the assessment of clinical effectiveness, as evidence relied mostly on small, single-arm, open-label studies. There were also several concerns in the cost-effectiveness evaluations, such as limited information on health-related quality of life, immature survival data due to short follow-up, and unclear curative potential. Substantial risk may be incurred with ATMPs, which have high upfront and possibly irrecoverable costs but uncertain long-term benefits. In conclusion, the challenges raised by the economic appraisal of ATMPs, albeit not unique, may be exacerbated by the uncertainty related to the often scant evidence base. Adaptations of the conventional decision-making process rather than completely new methods may improve appraisals of ATMPs.

Novel cell-based therapies in inflammatory bowel diseases: the established concept, promising results.

Inflammatory bowel diseases (IBDs) are chronic and relapsing disorders that affect the quality of life in many individuals around the world. Over the past few years, the prevalence of IBDs is substantially rising which might pose a considerable social and economic burden on health systems. Progresses in the management of chronic inflammatory diseases lead to prolonged remission phase and decreased hospitalization rate. However, during treatment, many patients become refractory to conventional therapies. Recently, advanced approaches using somatic cell therapy medicinal products (SCTMPs) including immune and stem cell-based therapies have drawn many researchers’ attentions. Promising results from recent trials, alongside with the emerging market indicated that these therapeutic approaches could be an alternative and promising treatment to conventional therapies. In this review, we will discuss recent advances in cell-based therapies, which have been developed for treatment of IBDs. In addition, the global emerging market and the novel products in this field are highlighted.

Acceptance of CRISPR-based technologies for clinical application: a Thematic Analysis of Attitudes on Novel Gene Therapies in Undergraduates

ABSTRACT CRISPR technologies are among the most powerful advancements in modern biology because they accurately manipulate the genomes of living cells and have the potential of curing various genetic diseases. This study examined the attitudes of undergraduate health science students towards somatic cell and germline gene editing therapies and whether supportive or critical supplemental literature differently influenced students’ stances. Fifty-two (n = 52) students were given a writing assignment where they were presented with two case scenarios involving their own hypothetical child who had been diagnosed with Duchenne muscular dystrophy. The first scenario presented students with the option for somatic cell therapy, while the second provided a cure using germline therapies. The responses were scored to determine the overall support for CRISPR therapies in these situations. A thematic analysis was conducted to determine what themes affected decision-making, and if supplemental readings affected outcomes. Findings showed that students were especially accepting of somatic cell therapies while half accepted germline therapies. The two most common themes from those accepting of CRISPR use were to ‘remove/prevent/treat human genetic diseases and cancer’, and to ‘improve quality of life’. Different types of supplemental literature did not affect the outcomes of this study.

Advanced Therapy Medicinal Products for the Eye: Definitions and Regulatory Framework.

Advanced therapy medicinal products (ATMPs) are a group of innovative and complex biological products for human use that comprises somatic cell therapy medicinal products, tissue engineered products, gene therapy medicinal products, and the so-called combined ATMPs that consist of one of the previous three categories combined with one or more medical devices. During the last few years, the development of ATMPs for the treatment of eye diseases has become a fast-growing field as it offers the potential to find novel therapeutic approaches for treating pathologies that today have no cure or are just subjected to symptomatic treatments. Therefore, it is important for all professionals working in this field to be familiar with the regulatory principles associated with these types of innovative products. In this review, we outline the legal framework that regulates the development of ATMPs in the European Union and other international jurisdictions, and the criteria that each type of ATMP must meet to be classified as such. To illustrate each legal definition, ATMPs that have already completed the research and development stages and that are currently used for the treatment of eye diseases are presented as examples.

Comparison of regulatory pathways for the approval of advanced therapies in the European Union and the United States

Background aimsRegulatory agencies in the European Union (EU) and in the United States of America (USA) have adapted and launched regulatory pathways to accelerate patient access to innovative therapies, such as advanced therapy medicinal products (ATMPs). The aim of this study is to analyze similarities and differences between regulatory pathways followed by the approved ATMPs in both regions. MethodsA retrospective analysis of the ATMPs approved by EU and US regulatory agencies was carried out until May 31, 2020. Data were collected on the features and timing of orphan drug designation (ODD), scientific advice (SA), expedited program designation (EP), marketing authorization application (MAA) and marketing authorization (MA) for both regions. ResultsIn the EU, a total of fifteen ATMPs were approved (eight gene therapies, three somatic cell therapies, three tissue-engineered products and one combined ATMP), whereas in the USA, a total of nine were approved (five gene therapies and four cell therapies); seven of these were authorized in both regions. No statistical differences were found in the mean time between having the ODD or EP granted and the start of the pivotal clinical trial or MAA in the EU and USA, although the USA required less time for MAA assessment than the EU (mean difference, 5.44, P = 0.012). The MAA assessment was shorter for those products with a PRIME or breakthrough designation.. No differences were found in the percentage of ATMPs with expedited MAA assessment between the EU and the USA (33.3% versus 55.5%, respectively, P = 0.285) or in the time required for the MAA expedited review (mean difference 4.41, P = 0.105). Approximately half of the products in both regions required an Advisory Committee during the MAA review, and 60% required an oral explanation in the EU. More than half of the approved ATMPs (67% and 55.55% in the EU and the USA, respectively) were granted an ODD, 70% by submitting preliminary clinical data in the EU. The mean number of SA and protocol assistance per product conducted by the European Medicines Agency was 1.71 and 3.75, respectively, and only 13% included parallel advice with health technology assessment bodies. A total of 53.33% of the products conducted the first SA after the pivotal clinical study had started, reporting more protocol amendments. Finally, of the seven ATMPs authorized in both regions, the type of MA differed for only two ATMPs (28.6%), and four out of eight products non-commercialized in the USA had a non-standard MA in the EU. ConclusionsThe current approved ATMPs mainly target orphan diseases. Although EU and US regulatory procedures may differ, the main regulatory milestones reached by the approved ATMPs are similar in both regions, with the exception of the time for MAA evaluation, the number of authorized products in the regions and the type of authorization for some products. More global regulatory convergence might further simplify and expedite current ATMP development in these regions.

Managing access to advanced therapy medicinal products: Challenges for NHS Wales.

Advanced Therapy Medicinal Products (ATMPs), which include gene, somatic cell therapies and tissue-engineered medicines, have the potential to transform current care pathways by offering durable and potentially curative outcomes. However, they are exceptionally expensive, with prices exceeding £1m per patient in some cases. With an expectation that a large number of ATMPs will soon gain marketing authorisation (global market is estimated to reach £9bn to £14bn by 2025), healthcare payers and providers face a number of challenges to facilitate patient access to this new category of medicines. This viewpoint reflects on the experience of introducing ATMPs into the National Health Service in Wales where £1 in every £200 spent on medicines (2019/2020) is expected to be on ATMPs for just 20 patients. Evidence to date makes it apparent that decisions regarding clinical and cost-effectiveness and the scale of the budget impact of implementing ATMPs create both financial and health service risks. Consequently, there are significant policy implications. A critical examination is made of the approaches taken for the health technology assessment and appraisal of ATMPs, the methods of payment and service impacts of these medicines, and the approach taken to horizon scanning and subsequent modelling of the financial impact over the next 10 years.

Application of Amniotic Stem Cells on an Acellular Dermal Matrix Scaffold in a Burned Patient: A Case Report

BackgroundAdvances in science have allowed newly created medicinal products based on gene therapy, somatic cell therapy, and tissue engineering to be used in the treatment of human diseases. December 2008 legislation aims to ensure they are both safe for patients and available throughout the European Union. Amniotic stem cells are designated by the European Medicines Agency Committee for Advanced Therapies as an advanced therapy medicinal product; therefore, production must be in accordance with Regulation (EC) No. 1394/2007 of the European Council of 13 November 2007 on advanced therapy medicinal products. ObjectivesThis article details preliminary results of innovative amniotic stem cell transplant (supported by an acellular dermal matrix [ADM] produced in-house with Suprathel wound and burn dressing) in a burn patient and compares them with results in a patient treated with allogeneic skin. Material and MethodsAmniotic stem cells were applied to a 40-year-old patient with IIb°/III° thermal burns of 36% of total body surface area and III°/IV° of 1%. Wound healing was assessed by histologic examination and the Bates-Jensen scale. Reduction in pain perception was verified by 10-point visual analog scale. Hospitalization time was compared to length of stay for patients treated with standard therapy. ResultsThe patient was discharged from hospital on the 12th day after surgery with complete wound healing (almost 2 times shorter than the control). ConclusionsThe use of amniotic stem cells and ADM may be the optimal method for burn treatment.