{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T17:55:06Z","timestamp":1792173306917,"version":"4.4.0"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,7,31]],"date-time":"2023-07-31T00:00:00Z","timestamp":1690761600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3389\/fphar.2023.1200808","type":"journal-article","created":{"date-parts":[[2023,7,31]],"date-time":"2023-07-31T20:02:25Z","timestamp":1690833745000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":39,"title":["Cell-based medicinal products approved in the European Union: current evidence and perspectives"],"prefix":"10.3389","volume":"14","author":[{"given":"Stefania","family":"Bellino","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"La Salvia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Francesca","family":"Cometa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosanna","family":"Botta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,7,31]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e334","DOI":"10.1016\/j.clml.2020.12.010","article-title":"Systematic review and meta-analysis of CD19-specific CAR-T cell therapy in relapsed\/refractory acute lymphoblastic leukemia in the pediatric and young adult population: Safety and efficacy outcomes","volume":"21","author":"Aamir","year":"2021","journal-title":"Clin. Lymphoma Myeloma Leuk."},{"key":"B2","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/j.tmrv.2019.08.003","article-title":"Anti-CD19 CAR T-cell therapy for B-cell non-hodgkin lymphoma","volume":"34","author":"Abramson","year":"2020","journal-title":"Transfus. Med. Rev."},{"key":"B3","doi-asserted-by":"publisher","first-page":"783122","DOI":"10.3389\/fneur.2021.783122","article-title":"The safety and efficacy of stem cell therapy as an emerging therapy for ALS: A systematic review of controlled clinical trials","volume":"12","author":"Aljabri","year":"2021","journal-title":"Front. Neurol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"e17236","DOI":"10.7759\/cureus.17236","article-title":"Effectiveness of stem cell therapies in improving clinical outcomes in patients with heart failure","volume":"13","author":"Bhawnani","year":"2021","journal-title":"Cureus"},{"key":"B5","doi-asserted-by":"publisher","first-page":"4789","DOI":"10.3390\/cancers13194789","article-title":"Real world evidence of CAR T-cell therapies for the treatment of relapsed\/refractory B-cell non-hodgkin lymphoma: A monocentric experience","volume":"13","author":"Casadei","year":"2021","journal-title":"Cancers"},{"key":"B6","doi-asserted-by":"publisher","first-page":"592","DOI":"10.1016\/j.jcyt.2020.04.092","article-title":"Advanced therapy medicinal product manufacturing under the hospital exemption and other exemption pathways in seven European Union countries","volume":"22","author":"Coppens","year":"2020","journal-title":"Cytotherapy"},{"key":"B7","doi-asserted-by":"publisher","first-page":"686","DOI":"10.1016\/j.jcyt.2022.03.007","article-title":"Patient access to and ethical considerations of the application of the European Union hospital exemption rule for advanced therapy medicinal products","volume":"24","author":"Cuende","year":"2022","journal-title":"Cytotherapy"},{"key":"B8","doi-asserted-by":"publisher","first-page":"867","DOI":"10.1097\/TP.0000000000004527","article-title":"Addressing risks derived from the commodification of substances of human origin: A European proposal applicable worldwide","volume":"107","author":"Cuende","year":"2023","journal-title":"Transplantation"},{"key":"B9","doi-asserted-by":"publisher","first-page":"756029","DOI":"10.3389\/fmed.2021.756029","article-title":"Cell therapy: Types, regulation, and clinical benefits","volume":"8","author":"El-Kadiry","year":"2021","journal-title":"Front. Med."},{"key":"B10","unstructured":"Advanced therapy medicinal products: Overview\n            EMA\n          2001"},{"key":"B12","volume-title":"Guideline on human cell-based medicinal products","author":"EMA","year":""},{"key":"B13","volume-title":"Guideline on safety and efficacy follow-up and risk management of advanced therapy medicinal products","author":"EMA","year":""},{"key":"B11","volume-title":"Reflection paper on classification of advanced therapy medicinal products","author":"EMA","year":""},{"key":"B46","unstructured":"Annex 1, summary of product characteristics (Provenge)\n            EMA"},{"key":"B50","unstructured":"Annex 1, summary of product characteristics (Zalmoxis)\n            EMA\n          2016"},{"key":"B41","unstructured":"Annex 1, summary of product characteristics (ChondroCelect)\n            EMA\n          2017"},{"key":"B45","unstructured":"Annex 1, summary of product characteristics (Maci)\n            EMA\n          2018"},{"key":"B37","unstructured":"Annex 1, summary of product characteristics (Abecma)\n            EMA\n          2021"},{"key":"B38","unstructured":"Annex 1, summary of product characteristics (Alofisel)\n            EMA"},{"key":"B39","unstructured":"Annex 1, summary of product characteristics (Breyanzi)\n            EMA"},{"key":"B40","unstructured":"Annex 1, summary of product characteristics (Carvykti)\n            EMA"},{"key":"B42","unstructured":"Annex 1, summary of product characteristics (Ebvallo)\n            EMA"},{"key":"B43","unstructured":"Annex 1, summary of product characteristics (holoclar)\n            EMA"},{"key":"B44","unstructured":"Annex 1, summary of product characteristics (kymriah)\n            EMA"},{"key":"B47","unstructured":"Annex 1, summary of product characteristics (Spherox)\n            EMA"},{"key":"B48","unstructured":"Annex 1, summary of product characteristics (Tecartus)\n            EMA"},{"key":"B49","unstructured":"Annex 1, summary of product characteristics (Yescarta)\n            EMA"},{"key":"B14","doi-asserted-by":"publisher","first-page":"100033","DOI":"10.1016\/j.ocarto.2020.100033","article-title":"Clinical outcome is significantly better with spheroid-based autologous chondrocyte implantation manufactured with more stringent cell culture criteria","volume":"2","author":"Eschen","year":"2020","journal-title":"Osteoarthr. Cartil. Open"},{"key":"B15","article-title":"Commission directive 2009\/120\/EC of 14 September 2009 amending directive 2001\/83\/EC of the European Parliament and of the council on the community code relating to medicinal products for human use as regards advanced therapy medicinal products","author":"European Commission","year":"2009","journal-title":"Off. J. Eur. Union"},{"key":"B16","volume-title":"Guidelines on good manufacturing practice for advanced therapy medicinal products","year":"2017"},{"key":"B17","unstructured":"EU clinical trials register\n            European Medicines Agency\n          2020"},{"key":"B18","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1007\/5584_2020_592","article-title":"Embryonic stem cells in clinical trials: Current overview of developments and challenges","volume":"1312","author":"Golchin","year":"2021","journal-title":"Adv. Exp. Med. Biol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"780","DOI":"10.14740\/jocmr3964","article-title":"Advanced therapy medicinal products challenges and perspectives in regenerative medicine","volume":"12","author":"Goula","year":"2020","journal-title":"J. Clin. Med. Res."},{"key":"B20","doi-asserted-by":"publisher","first-page":"2087","DOI":"10.1200\/jco.22.01365","article-title":"Idecabtagene vicleucel for relapsed\/refractory multiple myeloma: Real-world experience from the myeloma CAR T consortium","volume":"41","author":"Hansen","year":"2023","journal-title":"J. Clin. Oncol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"8996","DOI":"10.3390\/ijms22168996","article-title":"CAR T-cell therapy in hematological malignancies","volume":"22","author":"Haslauer","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B22","doi-asserted-by":"publisher","first-page":"772","DOI":"10.1016\/j.jcyt.2020.08.011","article-title":"An assessment of the hospital exemption landscape across European member States: Regulatory frameworks, use and impact","volume":"22","author":"Hills","year":"2020","journal-title":"Cytotherapy"},{"key":"B23","doi-asserted-by":"publisher","first-page":"631291","DOI":"10.3389\/fimmu.2021.631291","article-title":"Recent developments in clinical applications of mesenchymal stem cells in the treatment of rheumatoid arthritis and osteoarthritis","volume":"12","author":"Hwang","year":"2021","journal-title":"Front. Immunol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"3606","DOI":"10.1182\/bloodadvances.2021006922","article-title":"Real-world evidence of brexucabtagene autoleucel for the treatment of relapsed or refractory mantle cell lymphoma","volume":"6","author":"Iacoboni","year":"2022","journal-title":"Blood Adv."},{"key":"B25","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1016\/j.jcyt.2020.11.008","article-title":"Comparison of regulatory pathways for the approval of advanced therapies in the European Union and the United States","volume":"23","author":"Iglesias-Lopez","year":"2021","journal-title":"Cytotherapy"},{"key":"B26","doi-asserted-by":"publisher","first-page":"925985","DOI":"10.3389\/fimmu.2022.925985","article-title":"CAR T-cell-based gene therapy for cancers: New perspectives, challenges, and clinical developments","volume":"13","author":"Jogalekar","year":"2022","journal-title":"Front. Immunol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1089\/ten.TEB.2022.0094","article-title":"Issues with tissues: Trends in tissue-engineered products in clinical trials in the European union","volume":"29","author":"Joyce","year":"2023","journal-title":"Tissue Eng. Part B Rev."},{"key":"B28","doi-asserted-by":"publisher","first-page":"1004","DOI":"10.1089\/hum.2021.168","article-title":"Is hospital exemption an alternative or a bridge to European medicines agency for developing academic chimeric antigen receptor T-cell in europe? Our experience with ARI-0001","volume":"32","author":"Juan","year":"2021","journal-title":"Hum. Gene Ther."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1093","DOI":"10.21037\/atm-20-4502","article-title":"Challenges and strategies of clinical application of CAR-T therapy in the treatment of tumors-a narrative review","volume":"8","author":"Li","year":"2020","journal-title":"Ann. Transl. Med."},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2022.280482","article-title":"Adjusted comparison of outcomes between patients from CARTITUDE-1 versus multiple myeloma patients with prior exposure to PI, IMiD and anti-CD38 antibody from the prospective, multinational LocoMMotion study of real-world clinical practice","author":"Mateos","year":"2022","journal-title":"Haematologica"},{"key":"B31","doi-asserted-by":"publisher","first-page":"698607","DOI":"10.3389\/fonc.2021.698607","article-title":"Efficacy and safety of CAR-T cell products axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel for the treatment of hematologic malignancies: A systematic review and meta-analysis","volume":"11","author":"Meng","year":"2021","journal-title":"Front. Oncol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"e002056","DOI":"10.1136\/jitc-2020-002056","article-title":"Perspectives on outpatient administration of CAR-T cell therapy in aggressive B-cell lymphoma and acute lymphoblastic leukemia","volume":"9","author":"Myers","year":"2021","journal-title":"J. Immunother. Cancer"},{"key":"B33","unstructured":"Advanced therapy medicinal products observatory\n            Osservatorio Terapie Avanzate\n          2023"},{"key":"B34","doi-asserted-by":"publisher","first-page":"150","DOI":"10.36401\/JIPO-21-2","article-title":"Real-world experiences of CAR T-cell therapy for large B-cell lymphoma: How similar are they to the prospective studies?","volume":"4","author":"Tang","year":"2021","journal-title":"J. Immunother. Precis. Oncol."},{"key":"B51","unstructured":"Alofisel shows clinical remission rate in the real-world INSPIRE study2022"},{"key":"B35","doi-asserted-by":"publisher","first-page":"2320","DOI":"10.1016\/j.ymthe.2020.09.015","article-title":"CAR T cell therapy for solid tumors: Bright future or dark reality?","volume":"28","author":"Wagner","year":"2020","journal-title":"Mol. Ther."},{"key":"B36","doi-asserted-by":"publisher","first-page":"1295","DOI":"10.1002\/ajh.26301","article-title":"Efficacy and safety of CD19-directed CAR-T cell therapies in patients with relapsed\/refractory aggressive B-cell lymphomas: Observations from the JULIET, ZUMA-1, and TRANSCEND trials","volume":"96","author":"Westin","year":"2021","journal-title":"Am. J. Hematol."},{"key":"B52","doi-asserted-by":"publisher","first-page":"90521","DOI":"10.18632\/oncotarget.19361","article-title":"Chimeric-antigen receptor T (CAR-T) cell therapy for solid tumors: Challenges and opportunities","volume":"8","author":"Xia","year":"2017","journal-title":"Oncotarget"},{"key":"B53","doi-asserted-by":"publisher","first-page":"3994","DOI":"10.3390\/ijms21113994","article-title":"Clinical trials of stem cell treatment for spinal cord injury","volume":"21","author":"Yamazaki","year":"2020","journal-title":"Int. J. Mol. Sci."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2023.1200808\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,31]],"date-time":"2023-07-31T20:02:33Z","timestamp":1690833753000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2023.1200808\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,31]]},"references-count":53,"alternative-id":["10.3389\/fphar.2023.1200808"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2023.1200808","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,31]]},"article-number":"1200808"}}