Cytotherapy最新文献

{"title":"Yield-driven approach optimizes apheresis of CD19 chimeric antigen receptor-T cell therapy for patients with lymphoma","authors":"Tomoyasu Jo ,&nbsp;Toshio Kitawaki ,&nbsp;Takashi Sakamoto ,&nbsp;Chisaki Mizumoto ,&nbsp;Junya Kanda ,&nbsp;Momoko Nishikori ,&nbsp;Kouhei Yamashita ,&nbsp;Miki Nagao ,&nbsp;Akifumi Takaori-Kondo ,&nbsp;Yasuyuki Arai","doi":"10.1016/j.jcyt.2025.06.002","DOIUrl":"10.1016/j.jcyt.2025.06.002","url":null,"abstract":"<div><div>Leukapheresis for chimeric antigen receptor (CAR) T cell therapy requires optimization according to product-specific manufacturing requirements. We retrospectively analyzed 80 patients with large B-cell lymphoma, who underwent leukapheresis for tisagenlecleucel (tisa-cel, <em>n</em> = 31), lisocabtagene maraleucel (liso-cel, <em>n</em> = 29) or axicabtagene ciloleucel (axi-cel, <em>n</em> = 20) at Kyoto University Hospital between January 2022 and October 2024. Peripheral blood (PB) CD3⁺ cell counts before leukapheresis (median, 504/μL) and collection efficiencies (median, 62.1%) were similar among groups. The axi-cel group required significantly larger processing blood volumes (axi-cel, 12 L; liso-cel, 12 L; tisa-cel, 10 L; <em>P</em> &lt; 0.001) and longer processing times (axi-cel, 240 min; liso-cel, 204 min; tisa-cel, 203 min; <em>P</em> = 0.002), resulting in higher CD3⁺ cell yields. Moreover, the standard deviation of CD3⁺ cell yields was significantly larger in the axi-cel group (axi-cel, 3.04 × 10⁹ cells; liso-cel, 1.54 × 10⁹ cells; tisa-cel, 1.59 × 10⁹ cells; <em>P</em> = 0.003). The axi-cel group more frequently exceeded estimated blood volumes needed to achieve 5 × 10⁹ CD3⁺ cells (axi-cel, 45.0%; liso-cel, 17.2%; tisa-cel, 16.1%; <em>P</em> = 0.048). These findings highlight variability in leukapheresis procedures among CAR-T products. Protocols targeting cell yields based on PB cell counts may optimize blood volume to be processed so as to reduce patient burden.</div></div>","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":"27 10","pages":"Pages 1173-1178"},"PeriodicalIF":3.2,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144545869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Considerations driving the choice in clinical trial design of cell and gene therapy products: weighing convenience versus necessity","authors":"Keith Abrams ,&nbsp;Alessandro Aiuti ,&nbsp;Hans-Georg Eichler ,&nbsp;Andreas Ziegler","doi":"10.1016/j.jcyt.2025.06.001","DOIUrl":"10.1016/j.jcyt.2025.06.001","url":null,"abstract":"<div><div>Because of small patient populations, lack of effective therapies, and complicated treatment protocols, advanced therapy medicinal products (ATMPs) for rare diseases are often licensed based on evidence generated outside of a “gold standard” double-blinded, randomized controlled trial (RCT). The lack of important bias-reducing features in non-RCTs can present uncertainties for regulators and health technology assessment bodies, making choice of trial design a critical decision for developers. This “Meeting of the Minds,” co-hosted by the Alliance for Regenerative Medicine, the International Society for Cell &amp; Gene Therapy and ATMP Sweden in December 2024, set out to create a structured framework that provides clarity on when deviation from an RCT is necessary and should be acceptable, and on how alternative study designs such as a single-arm trial or unblinded RCT may be justified. Through multi-stakeholder engagement and discussions of case studies, a “trial-design decision tree” was generated that can help guide developers and healthcare decision-makers through a stepwise approach to contemplating deviation from an RCT. Although not exhaustive, three clinical scenarios surfaced where departure from a blinded RCT appears warranted: cases where the experimental treatment is expected to have high efficacy but the enrollable patient population is too small, cases where there is no effective standard of care and patients assigned to placebo would experience significant disease progression during the trial and cases where subjecting the control group to complex, burdensome and potentially risky protocols in the interest of blinding would impose unacceptable burden on patients.</div></div>","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":"27 10","pages":"Pages 1164-1172"},"PeriodicalIF":3.2,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144340600","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hospital Exemption in Italy: technical-scientific and regulatory aspects in comparison with Europe","authors":"Alessandra Ambrosone,&nbsp;Maria Francesca Cometa","doi":"10.1016/j.jcyt.2025.05.013","DOIUrl":"10.1016/j.jcyt.2025.05.013","url":null,"abstract":"<div><div>Hospital Exemption (HE) represents a regulatory tool that allows the use of advanced therapy medicinal products (ATMPs) prepared on an individual basis for the treatment of patients with an unmet medical need and without viable therapeutic alternatives. However, the regulatory framework governing this tool varies significantly among European countries while providing accelerated access to such treatments. This article aims to analyze the applications for treatment with ATMPs prepared in a non-repetitive modality over the 10-year period of 2015 to 2025, focusing on the proposed therapies and the clinical outcomes achieved. The data reviewed concern ATMPs authorized for individual patients by the Italian Medicines Agency on the basis of the opinion regarding suitability for use issued by the Phase I Committee established at the Istituto Superiore di Sanità, the Italian scientific technical body that supports the national health care system. Particular attention is given to the critical challenges encountered in the administration of the HE pathway in the 10 years since the regulation came into effect. In a European context of limited regulatory harmonization, this article explores issues currently being discussed in European regulatory boards and anticipates the implementation of some items, including a monitoring system. It highlights the main operational challenges in HE practices and proposes management solutions to optimize their implementation. Such solutions include the creation of a centralized monitoring database for tracking patients, medical conditions, and products used.</div></div>","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":"27 10","pages":"Pages 1251-1261"},"PeriodicalIF":3.2,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144334360","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical trial assessing the safety and efficacy of human bone marrow-derived allogeneic mesenchymal stem cell therapy for chronic active antibody-mediated rejection in kidney transplant recipients","authors":"Hyeran Park ,&nbsp;Xianying Fang ,&nbsp;Hanbi Lee ,&nbsp;Tae Hyun Ban ,&nbsp;Eun-Jee Oh ,&nbsp;Hye Eun Yoon ,&nbsp;Hyung Duk Kim ,&nbsp;Byung Ha Chung","doi":"10.1016/j.jcyt.2025.05.011","DOIUrl":"10.1016/j.jcyt.2025.05.011","url":null,"abstract":"<div><h3>Background aims</h3><div>This study evaluated the safety and efficacy of allogenic human bone marrow-derived mesenchymal stem cell (hBM-MSC) therapy in kidney transplant recipients (KTR) with chronic active antibody-mediated rejection (cABMR).</div></div><div><h3>Methods</h3><div><span>Seven cABMR patients received four infusions of hBM-MSC (1 × 10⁶ cells/kg), one every other week. The primary outcome was clinical safety, focusing on short-term adverse events. Secondary outcomes included changes in allograft<span><span> function, mean fluorescence intensity (MFI) of donor-specific anti-human leukocyte antigen antibodies<span><span> (HLA-DSA), allogenic immune response as determined by ELISPOT, </span>lymphocyte subset analysis, infection-free survival, and </span></span>graft survival compared to 18 historical controls via </span></span>propensity score matching.</div></div><div><h3>Results</h3><div><span><span><span>Seven patients received hBM-MSC therapy at a median of 5.4 years (range, 1.6-15.3) after KT<span> and 8.5 months (range, 1.2–20.6) after the diagnosis of cABMR. Six patients completed treatment, and one patient received two doses. No immediate side effects were observed. One patient developed Pneumocystis jirovecii pneumonia (PJP) 3 weeks after treatment and died 6 weeks post-treatment. Among those who completed therapy, the </span></span>eGFR slope shifted from –Δ16.6% to –Δ2.4% over the 6 month periods before and after treatment, suggesting a stabilization of eGFR decline, </span>proteinuria decreased, and MFI of HLA-DSA declined. T-cell subset analysis showed increased CD8+CD45RA+CCR7- </span>T cells and CD4+CD25+CD127low T cells with decreased CD8+CCR7+CD45RO+/CD45RA+ T cells. Kaplan–Meier analysis demonstrated no significant difference in infection-free survival or death-censored graft survival compared to those of the propensity score-matched control group. No significant difference in infection-free survival or death-censored graft survival compared to those of the propensity score-matched control group.</div></div><div><h3>Conclusions</h3><div>hBM-MSC therapy was generally well tolerated for KTR with cABMR and demonstrated favorable immunomodulatory effects. Larger, controlled trials with extended period are required to validate these findings and better define the role of hBM-MSC therapy for cABMR.</div></div>","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":"27 10","pages":"Pages 1199-1207"},"PeriodicalIF":3.2,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144638607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell microencapsulation improves lung retention of endothelial colony-forming cells after intravascular delivery and unmasks therapeutic benefit in severe pulmonary arterial hypertension","authors":"Nicholas D. Cober ,&nbsp;Ketul R. Chaudhary ,&nbsp;Yupu Deng ,&nbsp;Chyan-Jang Lee ,&nbsp;Katelynn Rowe ,&nbsp;Haya Abdelwahab ,&nbsp;David W. Courtman ,&nbsp;Duncan J. Stewart","doi":"10.1016/j.jcyt.2025.02.009","DOIUrl":"10.1016/j.jcyt.2025.02.009","url":null,"abstract":"<div><div>Pulmonary arterial hypertension (PAH) is triggered by pulmonary vascular endothelial cell apoptosis and microvascular loss. Therefore, therapies that can regenerate lost vasculature may offer therapeutic benefit. Endothelial colony–forming cells (ECFCs) can directly repair damaged blood vessels and may have therapeutic potential for the treatment of PAH. However, poor retention of ECFCs in the lungs following intravenous delivery greatly limits their therapeutic application. Therefore, we studied whether cellular microencapsulation could enhance retention in the lung after systemic delivery and improve therapeutic efficacy of ECFCs in a rat monocrotaline (MCT) PAH model. ECFCs were encapsulated by vortex emulsion using various concentrations of agarose, and initial cell viability was assessed. Encapsulated and free ECFCs were transduced with luciferase and administered to Sprague-Dawley rats 3 days after injection of MCT. In vivo ECFC persistence and bio-distribution was assessed by bioluminescence imaging (BLI). At the end of the study, right ventricular systolic pressure (RVSP) and right ventricular hypertrophy were assessed for therapeutic efficacy. Microgel encapsulation using 3.5% agarose improved cell survival and supported cell migration from capsules. At 15 minutes after delivery, BLI radiance was similar for free and microencapsulated ECFCs. However, only encapsulated cells could be detected by BLI at 4 and 24 hours. Transplantation of microencapsulated ECFCs led to significant improvement in RVSP 3 weeks after delivery compared with nonencapsulated ECFCs. Together, microencapsulation increased retention of ECFCs within the lungs. Furthermore, even a modest increase in ECFC persistence over 24 hours can provide an important therapeutic benefit in the rat MCT model of PAH.</div></div>","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":"27 6","pages":"Pages 723-732"},"PeriodicalIF":3.7,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143634939","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Center effect on outcomes of second allogeneic hematopoietic stem cell transplantation for B-cell acute lymphoblastic leukemia: a nationwide retrospective study","authors":"Shuhei Kurosawa ,&nbsp;Takahiro Fukuda ,&nbsp;Tatsuo Ichinohe ,&nbsp;Yoshiko Hashii ,&nbsp;Junya Kanda ,&nbsp;Hideki Goto ,&nbsp;Koji Kato ,&nbsp;Fumihiko Ishimaru ,&nbsp;Makoto Yoshimitsu ,&nbsp;Moeko Hino ,&nbsp;Keitaro Matsuo ,&nbsp;Yuri Ito ,&nbsp;Atsumi Yanagisawa ,&nbsp;Marie Ohbiki ,&nbsp;Ken Tabuchi ,&nbsp;Yoshiko Atsuta ,&nbsp;Yasuyuki Arai ,&nbsp;Japanese Society for Transplantation and Cellular Therapy (JSTCT)","doi":"10.1016/j.jcyt.2025.03.002","DOIUrl":"10.1016/j.jcyt.2025.03.002","url":null,"abstract":"<div><div>We evaluated the impact of center volume on outcomes in patients with B-cell acute lymphoblastic leukemia following their second allogeneic hematopoietic stem cell transplantation (allo-HSCT). Our cohort included 299 patients with relapse and 68 patients with graft failure after their first allo-HSCT between 2003 and 2017. Patients were stratified into low- and high-volume groups based on the number of allo-HSCT performed at each center. The primary endpoint was 5-year overall survival (OS) following the second allo-HSCT. In the relapse cohort, the high-volume group demonstrated significantly better 5-year OS (21.1% vs 13.6%, <em>P</em> = 0.0062) and progression-free survival (16.1% vs 10.6%, <em>P</em> = 0.010). Multivariate analysis showed that high-volume group was a favorable factor for OS (hazard ratio [HR]: 0.72, 95% confidence interval [CI]: 0.56–0.94, <em>P</em> = 0.016). This survival benefit was consistent in both Philadelphia chromosome-negative (HR: 0.71, 95% CI: 0.51–0.99, <em>P</em> = 0.042) and positive (HR: 0.61, 95% CI: 0.39–0.95, <em>P</em> = 0.030) subcohorts. In the graft failure cohort, the high-volume group showed a trend toward better 5-year OS (41.6% vs 24.4%, <em>P</em> = 0.098) and lower 5-year nonrelapse mortality (NRM) (55.9% vs 75.6%, <em>P</em> = 0.067). Multivariate analysis confirmed the protective effect of the high-volume group on NRM (HR: 0.55, 95% CI: 0.30–0.99, <em>P</em> = 0.044). Our findings demonstrate that center volume significantly impacts outcomes after the second allo-HSCT regardless of indication, highlighting the need for inter-center collaboration and standardized management strategies for this high-risk population.</div></div>","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":"27 6","pages":"Pages 733-743"},"PeriodicalIF":3.7,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143744348","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aims and Scope","authors":"","doi":"10.1016/S1465-3249(25)00726-1","DOIUrl":"10.1016/S1465-3249(25)00726-1","url":null,"abstract":"","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":"27 6","pages":"Page A1"},"PeriodicalIF":3.7,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144298220","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DNA-dependent protein kinase inhibitors PI-103 and samotolisib augment CRISPR/Cas9 knock-in efficiency in human T cells","authors":"Emina Džafo ,&nbsp;Morteza Hafezi ,&nbsp;Greta Maria Paola Giordano Attianese ,&nbsp;Patrick Reichenbach ,&nbsp;Stephane Grillet,&nbsp;Hélène Garcia,&nbsp;Elisabetta Cribioli,&nbsp;Christel Voize,&nbsp;Stephanie Tissot,&nbsp;Romain Vuillefroy de Silly,&nbsp;George Coukos,&nbsp;Kirsten Scholten,&nbsp;Melita Irving ,&nbsp;Bernhard Gentner","doi":"10.1016/j.jcyt.2025.02.001","DOIUrl":"10.1016/j.jcyt.2025.02.001","url":null,"abstract":"<div><div>The adoptive transfer of autologous peripheral blood T cells gene-modified to express preselected, tumor antigen–specific T-cell receptors (TCRs) is a promising treatment for solid cancers. While gene-transfer by viral transduction is highly efficient, the insertional site is not targeted and persistence of the T cells is oftentimes limited. In contrast, site-specific integration of the TCR into the TCR α chain (<em>TRAC</em>) locus by CRISPR/Cas9 has been shown to enable more consistent and physiologic levels of exogenous TCR expression coupled with superior persistence and tumor control in preclinical studies. Here, we sought to improve the efficiency of CRISPR/Cas9 mediated TCR knock-in (KI) into the <em>TRAC</em> locus of primary human T cells. In addition to the previously reported DNA-dependent protein kinase (DNA-PK) inhibitor M3814, we demonstrated that PI-103 and samotolisib markedly increase KI efficiency in a process that is good manufacturing process (GMP)–compatible. Importantly, samotolisib enabled the generation of a potent T-cell product, having no negative impact on T-cell viability, phenotype, expansion, effector function, and tumor control. Overall, we conclude that our GMP-compatible CRISPR/Cas9 protocol comprising samotolisib to augment TCR KI efficiency is suitable for the generation of genetically modified T cells for clinical use.</div></div>","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":"27 6","pages":"Pages 766-773"},"PeriodicalIF":3.7,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143658978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The current state of Cytotherapy and the field of cell and gene therapy","authors":"William Y.K. Hwang ,&nbsp;Ezzah Mohamed Muzammil","doi":"10.1016/j.jcyt.2025.01.017","DOIUrl":"10.1016/j.jcyt.2025.01.017","url":null,"abstract":"<div><div>2024 marked a transformative phase for cell and gene therapy (CGT) with significant advancements in scientific innovation, regulatory approvals and commercialization milestones. This review highlights key developments in CGT, including innovations in chimeric antigen receptor (CAR)-T therapies, mesenchymal stromal cells (MSCs), gene editing and regenerative medicine, alongside challenges in scalability, regulation and safety. Prominent breakthroughs in CAR-T technology extended its applications beyond oncology to autoimmune diseases, including lupus and systemic sclerosis. Gene therapies achieved major milestones, exemplified by regulatory approval for the treatment of hemophilia, sickle cell disease and other genetic diseases. Further advancements in delivery systems, including lipid nanoparticles and engineered viral vectors were achieved. Refinements in clustered regularly interspaced short palindromic repeats-Cas9 and base-editing tools improved precision and reduced off-target effects, enabling new approaches for genetic disorders. Global collaboration underscored the collective effort to accelerate CGT progress. MSCs remain central to CGT research, focusing on their immunomodulatory properties and clinical applications in autoimmune diseases and graft-versus-host disease. Economic and policy landscapes evolved alongside scientific advancements. Record-breaking approvals and biotech IPOs underscored CGT's economic potential, while affordability and equitable access emerged as critical challenges. Regulatory agencies advanced harmonized guidelines for manufacturing and clinical evaluation, streamlining global access to these therapies. Ethical considerations, including the affordability of therapies and the need for diverse clinical trial representation, remained prominent. Despite progress, challenges persist in scalability, safety and regulatory harmonization. Manufacturing improvements are essential to meet growing demand, while addressing safety concerns, such as off-target gene-editing effects and tumorigenicity in MSC therapies, remains paramount.</div></div>","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":"27 6","pages":"Pages 678-685"},"PeriodicalIF":3.7,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143568775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulatory advancements in Japan's conditional and time-limited approval scheme for regenerative medical products: the first guidance on the approval scheme and the second review for full approval of the first conditional and time-limited approved cellular product, HeartSheet","authors":"Shinichi Noda ,&nbsp;Yoko Kobayashi ,&nbsp;Narumi Okura ,&nbsp;Kayo Shinohara ,&nbsp;Junichi Asano ,&nbsp;Jun Matsumoto","doi":"10.1016/j.jcyt.2025.02.010","DOIUrl":"10.1016/j.jcyt.2025.02.010","url":null,"abstract":"<div><div>In Japan, the Act on Securing Quality, Efficacy, and Safety of Products including Pharmaceuticals and Medical Devices (PMD Act) provides the option for an expedited approval scheme, conditional and time limited, for regenerative medical products only. In March 2024, the Guidance for Conditional and Time-Limited Approval for Regenerative Medical Products and the Development of Subsequent Efficacy Evaluation Plan was established by the Ministry of Health, Labor and Welfare (MHLW). This document is the first guidance on the approval scheme, providing information such as specific examples of the scope of this scheme as well as an indication of what should be considered in the post-marketing approval condition assessment. HeartSheet—a human (autologous) skeletal myoblast-derived cell sheet—was the first product approved through the conditional and time-limited approval scheme. After the second review by the Pharmaceuticals and Medical Devices Agency (PMDA) based on post-marketing data, the MHLW decided in July 2024 that the product had not demonstrated efficacy and that full approval was not appropriate. This is the first time that post-marketing data have been considered for the full approval of a conditional and time-limited approval product. This decision demonstrates that the conditional and time-limited approval scheme is strictly enforced. This article describes key points of the guidance on the conditional and time-limited approval scheme and the PMDA's full approval review experience with HeartSheet. These regulatory actions will further deepen the understanding of the conditional and time-limited approval scheme, especially among developers, and promote more appropriate use of the scheme.</div></div>","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":"27 6","pages":"Pages 700-708"},"PeriodicalIF":3.7,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143659120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}