Cytotherapy最新文献

{"title":"Key considerations for dose selection in first-in-human studies of cell and gene therapy products.","authors":"Misaki Naota, Yusuke Nozaki, Fumito Mikashima, Gen Higashiyama","doi":"10.1016/j.jcyt.2025.06.012","DOIUrl":"https://doi.org/10.1016/j.jcyt.2025.06.012","url":null,"abstract":"<p><p>Advancements in science and technology have led to the development of cell and gene therapy (CGT) products with diverse modalities and mechanisms of action (MOAs). However, this diversity presents significant challenges for standardizing dose selection in clinical studies based solely on nonclinical data. Moreover, extrapolating nonclinical efficacy and safety data to humans is often unreliable. In first-in-human (FIH) studies, these limitations necessitate robust quality characterization, nonclinical proof-of-concept (POC) studies, and a comprehensive understanding of each product's MOA, with dose determination tailored to each product. In this review article, we aim to examine the critical factors influencing the extrapolation of nonclinical data to humans, highlight limitations of such extrapolation, and present specific examples of dose-setting approaches for FIH studies of CGT products. We outline key considerations for dose selection, emphasizing the importance of considering product-specific characteristics and MOA. Understanding these aspects of CGT products facilitates the design of appropriate nonclinical studies and supports accurate interpretation of their outcomes, ultimately contributing to the safe execution of FIH studies involving CGT products.</p>","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144790569","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":"Hypoimmune FK binding protein 12-knockout CD19 CAR T cells achieve deep tissue B-cell depletion and control Nalm6 tumors in immunosuppressed humanized mice","authors":"Xiaomeng Hu ,&nbsp;Andrew McAlister ,&nbsp;Jeremy Kinder ,&nbsp;Adam Johnson ,&nbsp;Kathy White ,&nbsp;Carolin B. Caruso ,&nbsp;Chenyan Wang ,&nbsp;Ron Basco ,&nbsp;Corie Gattis ,&nbsp;Annabelle Friera ,&nbsp;Tobias Deuse ,&nbsp;Sonja Schrepfer","doi":"10.1016/j.jcyt.2025.06.013","DOIUrl":"10.1016/j.jcyt.2025.06.013","url":null,"abstract":"<div><div>Autologous chimeric antigen receptor (CAR) T-cell therapy in solid-organ transplant recipients on life-long systemic immunosuppression has so far been disappointing. The mTOR inhibitors tacrolimus (Tac) and rapamycin (Rapa) are among the most common immunosuppressive drugs. While they prevent organ allograft rejection, they also suppress the efficacy and persistence of the CAR T-cell product. A reduction in immunosuppression is usually recommended before leukapheresis and after infusion of the final CAR therapeutic to facilitate CAR T-cell activity. However, this reduction jeopardizes allograft survival and multiple graft failures have been reported. Here, we report the engineering of allogeneic, human CD19 CAR T cells that are resistant to mTOR inhibitors through the knockout of FK-binding protein 12 (FKBP-KO). Both HLA-replete WT-FKBP-KO and hypoimmune (HLA class I- and II-depleted and CD47-overexpressing, HIP) CD19 CAR T cells maintained effective <em>in vitro</em> killing capacity of benign human B cells and malignant Nalm6 tumor cells when incubated with high Tac and Rapa concentrations. CAR T cells without the FKBP-KO failed to kill both targets in the presence of Tac or Rapa. HIP-FKBP-KO CAR T cells were able to fully evade cytotoxicity from primed allogeneic T cells, natural killer (NK cells), and macrophages. When injected into immunosuppressed Nalm6-bearing humanized mice, only the HIP-FKBP-KO CAR T cells achieved persistence and deep tissue depletion of CD19⁺ cells over a 25-day study period, whereas the WT-FKBP-KO CAR T cells diminished in number and efficacy. Allogeneic HIP-FKBP-KO CAR T cells may treat post-transplant lymphoproliferative disease effectively in solid organ transplant recipients maintained on immunosuppression.</div></div>","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":"27 10","pages":"Pages 1190-1198"},"PeriodicalIF":3.2,"publicationDate":"2025-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144621085","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":"Impact of ATLG on CD4+ T-cell reconstitution after HSCT in children: a detailed immune profiling study","authors":"Marco M. Sindoni ,&nbsp;Anita Toso ,&nbsp;Francesca Limido ,&nbsp;Cristina Bugarin ,&nbsp;Tiziana Villa ,&nbsp;Sarah Bonte ,&nbsp;Yvan Saeys ,&nbsp;Chiara Buracchi ,&nbsp;Giulia Prunotto ,&nbsp;Virginia Meda Spaccamela ,&nbsp;Mathias Hauri ,&nbsp;Oscar Maglia ,&nbsp;Simona Sala ,&nbsp;Domenico Gaspari ,&nbsp;Grazia Fazio ,&nbsp;Andrea Biondi ,&nbsp;Adriana Balduzzi ,&nbsp;Silvia Nucera ,&nbsp;Giuseppe Gaipa","doi":"10.1016/j.jcyt.2025.06.009","DOIUrl":"10.1016/j.jcyt.2025.06.009","url":null,"abstract":"<div><h3>Introduction</h3><div>Graft versus host disease (GvHD) prophylaxis impacts on post–hematopoietic stem cell transplantation (HSCT) immune reconstitution (IR). Specifically, anti-T lymphocyte globulin (ATLG) delays CD4⁺ T cell reconstitution. However, the mechanism by which ATLG alters the composition of CD4⁺ T-cell compartments remains elusive.</div></div><div><h3>Aims</h3><div>Dissect the impact of ATLG on CD4⁺ T cells by integrating advanced and highly standardized flow cytometric panels, unsupervised clustering analysis, machine learning approaches, and molecular biology techniques.</div></div><div><h3>Results</h3><div>We analyzed post-HSCT IR in 94 pediatric patients with a machine learning approach. ATLG exposure resulted in the most relevant variable affecting CD4⁺ T-cell counts. Severe combined immunodeficiency/recent thymic emigrant (SCID/RTE) and CD4 PERISCOPE EuroFlow antibody panels were applied to a sub-cohort of patients with acute lymphoblastic leukemia. Unsupervised clustering analysis showed that in the first months, post-HSCT CD4⁺ naïve T cells and RTEs were significantly reduced in ATLG-treated compared to no-ATLG patients, including haploidentical graft recipients receiving post-transplant cyclophosphamide. In no-ATLG patients, there was a significant contribution of residual recipient-derived cells to the RTE compartment, whereas in ATLG-treated patients RTEs were of donor origin. In addition, in no-ATLG patients, early RTEs and CD4⁺ T-cell counts correlated with infused CD3⁺ T cells/kg. Bone marrow and T-cell receptor excision circle (TREC) analysis showed that ATLG treatment does not affect early T-cell maturation. <em>In vitro</em> testing showed increased differentiation of naïve/RTE CD4⁺ into effector subsets upon ATLG exposure, confirmed by flow cytometry and RNA sequencing.</div></div><div><h3>Discussion</h3><div>Our data show that ATLG induces concomitant differentiation and depletion of the peripheral CD4⁺ naïve/RTE T-cell compartment. Together, these findings suggest that naïve T-cell reconstitution after ATLG is delayed since it only relies on thymic maturation, differently from no-ATLG treated patients.</div></div>","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":"27 10","pages":"Pages 1208-1218"},"PeriodicalIF":3.2,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144644011","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":"Advancing gene-editing platforms to improve the viability of rare-disease therapeutics: key insights from a 2024 Scientific Exchange hosted by ARM, ISCT, and Danaher","authors":"Fyodor Urnov ,&nbsp;Sadik Kassim ,&nbsp;Kiran Musunuru ,&nbsp;David Liu ,&nbsp;Ann Lee ,&nbsp;Luis Barrera ,&nbsp;Pam Stetkiewicz ,&nbsp;Julianne Bruno ,&nbsp;Matthew Hewitt ,&nbsp;Troy Lister ,&nbsp;Harry Malech ,&nbsp;Lindsay Gasch ,&nbsp;Matt Diver ,&nbsp;Nicholas Gertler ,&nbsp;Felix Grignon ,&nbsp;Audrey Le ,&nbsp;Michael Lehmicke ,&nbsp;Vanessa Almendro-Navarro ,&nbsp;Josephine Lembong","doi":"10.1016/j.jcyt.2025.06.010","DOIUrl":"10.1016/j.jcyt.2025.06.010","url":null,"abstract":"<div><div>Rare-disease therapeutics face viability challenges due to small patient populations and drug-development and regulatory frameworks that were not developed to address rapidly progressive or quickly fatal conditions. Because the majority of rare diseases are genetic in nature, gene-editing modalities offer substantial promise. This Scientific Exchange, co-hosted by the Alliance for Regenerative Medicine, the International Society for Cell and Gene Therapy, and Danaher Corporation in November 2024, set out to address the challenge of realizing the full promise of gene editing for rare-disease therapies by advancing platforms that leverage stable and reusable processes or components to develop multiple therapies. Through multi-stakeholder engagement and discussions of case studies in CRISPR/Cas nuclease, base, and prime editing, 4 key opportunities emerged that deliver value by holding platform elements constant and/or streamlining development steps: (1) consistent delivery vehicle; (2) consistent manufacturing; (3) benefit-risk appropriate quality requirements; and (4) expansive clinical trial designs. Together, these opportunities could yield up to 5-fold efficiency gains and result in substantial value creation for patients, regulators, and developers, potentially decreasing the time required to dose patients with a new gene-editing therapy from years down to 6 months.</div></div>","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":"27 10","pages":"Pages 1151-1163"},"PeriodicalIF":3.2,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144568040","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 manufacture of CRISPR/Cas9-based cytokine-induced SH2 protein knock-out tumor-infiltrating lymphocytes for gastrointestinal cancers","authors":"Matthew J. Johnson ,&nbsp;Darin Sumstad ,&nbsp;Timothy D. Folsom ,&nbsp;Nicholas J. Slipek ,&nbsp;Anthony P. DeFeo ,&nbsp;Molly Growe ,&nbsp;Diane Kadidlo ,&nbsp;Bharat Thyagarajan ,&nbsp;Timothy K. Starr ,&nbsp;Emil Lou ,&nbsp;Modassir Choudhry ,&nbsp;Branden S. Moriarity ,&nbsp;Beau R. Webber ,&nbsp;David H. McKenna","doi":"10.1016/j.jcyt.2025.06.007","DOIUrl":"10.1016/j.jcyt.2025.06.007","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Introduction&lt;/h3&gt;&lt;div&gt;The prognosis of stage IV gastrointestinal (GI) carcinomas is poor with a 15% five-year survival rate for colorectal carcinomas. To improve efficacy of tumor infiltrating lymphocytes (TIL), we isolated mutation-reactive autologous TIL and employed CRISPR/Cas9 to knockout (KO) the intracellular checkpoint protein &lt;em&gt;CISH&lt;/em&gt;, which has been shown to enhance T cell expansion, functional avidity, and cytokine polyfunctionality, with consequent durable regression of established tumors in an animal model.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Materials &amp; Methods&lt;/h3&gt;&lt;div&gt;TIL cultures were initiated from resected tumor fragments and maintained for six weeks before harvest and cryopreservation. Candidate neoantigens were nominated by exome sequencing and peptides were used to identify mutation reactive (MR) TIL. Selected MR TIL were thawed and allowed to recover for 24–36 h in media with 10% AB serum, 6000 IU/mL IL-2, and 5 ng/mL IL-7 and IL-15 followed by stimulation with plate-bound anti-CD3/soluble anti-CD28 for 4 days. &lt;em&gt;CISH&lt;/em&gt; KO was performed by electroporation of Cas9 mRNA and chemically modified single guide RNA. Between 5 -7.5 million viable cells were added to each 100 cm&lt;sup&gt;2&lt;/sup&gt; G-Rex vessel containing 600 mL expansion media (with allogeneic feeder MNC:TIL = 100:1) and incubated for 6–8 days. Cultures were evaluated and split according to cell concentration criteria (and dose cohort) and incubated for an additional 6-8 days. On day 14, all of the cells were harvested, washed with buffer and cryopreserved (5% DMSO). Lot release testing included: viability, %CD3+, cytology review, Gram stain, sterility, endotoxin, mycoplasma, and interferon gamma (IFN-γ) production. Additional testing included DNA sequencing to determine genomic &lt;em&gt;CISH&lt;/em&gt; editing efficiency and a Western blot for determination of CISH protein loss.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Patients with GI cancers (colon [10], rectal [8], pancreatic [1], and esophageal [1]) underwent tumor collection. Nineteen of 22 tumor biopsies sampled from 20 patients total proceeded to KO/expansion. Final TIL product results (mean [SD], median [range]) were: viable count (x 10&lt;sup&gt;10&lt;/sup&gt;) -3.25 (3.67), 1.95 (0.018–12.40); viable TIL fold expansion -327.1 (364.8), 153.1 (8–1454); % viability - 76 (13), 78 (43–92); % CD3 -94.4 (5.4), 95.8 (78.6–99.4); % &lt;em&gt;CISH&lt;/em&gt; KO efficiency – 75 (29), 87 (0–96); % editing efficiency - 59.9 (24.8), 66.9 (0.4–86). Viability fell below 70% for five TIL products. All other lot release testing has met specification. Thirteen patients have received TIL; six patients were not treated due to disease progression prior to anticipated infusion.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;The translation of CRISPR/Cas9-based &lt;em&gt;CISH&lt;/em&gt; KO MR TIL from the basic research lab to current good manufacturing practices The (cGMP) facility was successful, allowing for optimized, large-scale expansion in support of a first-in-human clinical tri","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":"27 10","pages":"Pages 1229-1239"},"PeriodicalIF":3.2,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144651124","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":"Mapping the European landscape and specificity of ATMPs guidance","authors":"Aurélie Mahalatchimy ,&nbsp;Valentin Roby ,&nbsp;Julie Véran ,&nbsp;Christian Chabannon ,&nbsp;Florence Sabatier","doi":"10.1016/j.jcyt.2025.06.008","DOIUrl":"10.1016/j.jcyt.2025.06.008","url":null,"abstract":"&lt;div&gt;&lt;div&gt;A good amount of guidance has been issued by various national and international organizations in addition to the global regulation of Advanced Therapy Medicinal Products (ATMPs) at the European Union (EU) level. These include regulatory, technical, and scientific documents (mainly, but not only, guidelines), which aim to support the operability of the European pharmaceutical legislative framework. Guidance documents are highly necessary, especially in a rapidly evolving field such as ATMPs in which scientific achievements may translate quickly into therapeutic innovations. They provide the needed flexibility and adaptation that the legislative level could never afford to the same extent when considering the usual delays for revision, adoption, and application of binding legislative acts such as the ATMPs Regulation or the European Directives on medicinal products. This has led to the early adoption of guidance documents in the field of gene and cell therapy, the first of which appeared in the 1990s. However, with this early adoption comes complexity and difficult readability due to the accumulation of new soft law rules in the wake of new scientific findings and hard law regulations. Our study provides the first comprehensive analysis of guidance produced and currently applicable in the field of ATMPs and its relationship with categorization of biological medicinal products. We base our analysis on the collection of available guidance documents from the websites of the most active institutions in the production of guidance on ATMPs applicable within the European Union. We also obtained relevant material via the search engines of those websites by using a list of keywords corresponding to ATMPs or their subcategories.&lt;/div&gt;&lt;div&gt;Our search resulted in a collection of 126 guidance documents applicable to ATMPs from July 1990 to September 8, 2023. We found that the distribution of current ATMP guidance mainly comes from the European Medicines Agency (EMA) and the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use regarding their sources, and are mainly guidelines regarding their types. This demonstrates that for the majority of currently applicable ATMP guidance documents, there is no overlap with other categories of biologicals, indicating that they are strictly specific to ATMPs. Our data indicate that the overlap between ATMPs and other biologicals essentially deals with the active substance and finished products among transversal categories and with biotechnologicals among various types of biological medicinal products. We discuss these results in light of their usefulness in regard to medical and socioeconomic actors of biotherapies.&lt;/div&gt;&lt;div&gt;Finally, we conclude that the singularity of ATMPs is quite well reflected through their guidance landscape with a high number and diversity of documents. Although the overlap of guidance applicable to biologicals is important and could be anticipa","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":"27 10","pages":"Pages 1262-1269"},"PeriodicalIF":3.2,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144592855","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":"Large-scale manufacturing of immunosuppressive extracellular vesicles for human clinical trials","authors":"Meizhang Li ,&nbsp;Rupal Soder ,&nbsp;Sunil Abhyankar ,&nbsp;Trisha Home ,&nbsp;Harsh Pathak ,&nbsp;Xingqi Shen ,&nbsp;Andrew K. Godwin ,&nbsp;Haitham Abdelhakim","doi":"10.1016/j.jcyt.2025.06.003","DOIUrl":"10.1016/j.jcyt.2025.06.003","url":null,"abstract":"<div><h3>Background</h3><div>Human mesenchymal stromal cells (MSCs), particularly Wharton's jelly-derived MSCs (WJMSCs), offer significant therapeutic potential for complex immune conditions such as graft versus host disease (GVHD), in part through their secreted small extracellular vesicles (sEVs). These sEVs exhibit crucial immunomodulatory properties, including suppression of T-cell activation demonstrated both in healthy donor cells and in pathologic contexts. Despite this promise, widespread clinical application is impeded by substantial challenges in developing robust, scalable, and Good Manufacturing Practice (GMP)–compliant manufacturing processes for MSC-derived sEVs to meet clinical demand.</div></div><div><h3>Methods</h3><div>To address the critical barriers in sEV production, this study details the development and validation of a reliable and scalable manufacturing platform for WJMSC-derived sEVs. The process utilized GMP expanded WJMSC culture medium, generated from cultured low-passage cells and processed in scalable 2-L and 6-L batch volumes. This platform employed a sequential approach involving tangential flow filtration (TFF) for efficient initial concentration followed by size-exclusion chromatography (SEC) for comprehensive final purification of sEVs.</div></div><div><h3>Results</h3><div>The integrated TFF-SEC manufacturing approach resulted in a significant enrichment of nanoparticles, demonstrating up to a 16.9- and 36-fold increase in particle concentration post-TFF from the 2-L and 6-L batches, respectively. Two batches of purified sEVs demonstrated very similar mean size ranges, from 142 ± 2 nm to 156 ± 2 nm, and displayed the markers CD9 and CD81 while not expressing the negative marker calnexin. Those WJMSC-derived sEVs maintained their biological activity, effectively suppressing - cell activation <em>in vitro</em>. Furthermore, the purified sEVs from both 2-L and 6-L batches demonstrated an intact structure observed by cryogenic electron microscopy (cryo-EM), positivity for the inhibitory immune checkpoint ligand PD-L1.</div></div><div><h3>Conclusion</h3><div>In this study, we report a reliable large-scale manufacturing framework that combines TFF and SEC to manufacture WJMSC-derived sEVs. The established standard operating procedures (SOPs) will help guide the design and establishment of industrial-scale, clinical-grade WJMSC-derived sEV manufacturing. This work significantly advances the field by offering a practical pathway that is anticipated to facilitate the broader development and accelerate the clinical translation of these WJMSC-derived sEVs as potent, cell-free therapeutic agents for various human diseases.</div></div>","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":"27 10","pages":"Pages 1219-1228"},"PeriodicalIF":3.2,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144530833","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":"CAR-NK cells to treat patients with cancer: a systematic scoping review of published studies and registered clinical trials","authors":"Simrit Rana ,&nbsp;Lilli Thomas ,&nbsp;Aidan M. Kirkham ,&nbsp;Risa Shorr ,&nbsp;Alissa Visram ,&nbsp;Harinad Maganti ,&nbsp;Matthew Seftel ,&nbsp;David S. Allan","doi":"10.1016/j.jcyt.2025.06.006","DOIUrl":"10.1016/j.jcyt.2025.06.006","url":null,"abstract":"<div><h3>Introduction</h3><div>Chimeric antigen-receptor natural killer cells (CAR-NKs) offer a promising allogeneic immune effector cell therapy to treat malignant diseases. A systematic review is needed to understand the scope of current clinical studies and registered active trials to identify aspects of study design and cell product characterization that could accelerate greater clinical adoption.</div></div><div><h3>Methods</h3><div>A systematic review of all publications (to January 25, 2025) and registered clinical trials (to June 21, 2024) was conducted. We extracted information on study design, patient characteristics, outcome measures, and cell product characterization.</div></div><div><h3>Results</h3><div>A total of 150 patients in ten studies published between 2018 and 2025 were identified. Hematologic malignancies were examined most frequently (n = 6 studies). All published studies were uncontrolled, and only four reported on more than three patients. CAR-NK products were most frequently derived from the NK-92 cell line (four studies), umbilical cord blood (three studies), induced pluripotent stem cells (one study), or not reported (two studies). Considerable heterogeneity was observed regarding CAR-NK cell manufacturing methods and dosing. Complete response rates for patients with B cell lymphomas ranged from 25–85%, depending on lymphoma subtype. Responses were durable with median response not reached in the largest study and durable remission at 1-year in 70% of responders in a second study. Adverse events were uncommon with no cases of grade 3 or higher cytokine release syndrome and no cases of immune effector-cell mediated neurotoxicity or graft versus host disease reported. Among the 50 registered trials identified (n=2102 subjects to be enrolled), hematological malignancies (n = 34; 68%) were the most common diseases examined.</div></div><div><h3>Conclusions</h3><div>The clinical outcomes and low adverse event rates following CAR-NK therapy in published studies are encouraging. Larger controlled trials are needed to confirm the safety and efficacy of CAR-NK therapy. We anticipate the completion of several such trials in the coming years.</div></div>","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":"27 10","pages":"Pages 1179-1189"},"PeriodicalIF":3.2,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144592854","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":"Corrigendum to scoring system for optimal cord blood unit selection for single cord blood transplantation cytotherapy 26 (2024) 286-298","authors":"Mizuki Watanabe ,&nbsp;Takaaki Konuma ,&nbsp;Nobuhiko Imahashi ,&nbsp;Seitaro Terakura ,&nbsp;Sachiko Seo ,&nbsp;Satoko Morishima ,&nbsp;Naoyuki Uchida ,&nbsp;Noriko Doki ,&nbsp;Masatsugu Tanaka ,&nbsp;Tetsuya Nishida ,&nbsp;Toshiro Kawakita ,&nbsp;Tetsuya Eto ,&nbsp;Satoshi Takahashi ,&nbsp;Masashi Sawa ,&nbsp;Yasufumi Uehara ,&nbsp;Sung Won Kim ,&nbsp;Fumihiko Ishimaru ,&nbsp;Tatsuo Ichinohe ,&nbsp;Takahiro Fukuda ,&nbsp;Yoshiko Atsuta ,&nbsp;Junya Kanda","doi":"10.1016/j.jcyt.2025.06.004","DOIUrl":"10.1016/j.jcyt.2025.06.004","url":null,"abstract":"","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":"27 10","pages":"Page 1270"},"PeriodicalIF":3.2,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144545868","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":"Efficacy and safety of etoposide + cytarabine + pegfilgrastim mobilization regimen versus G-CSF mobilization regimen alone for hematopoietic stem cell mobilization in patients with multiple myeloma and lymphoma","authors":"Sishi Xu ,&nbsp;Yixuan Cheng ,&nbsp;Renzhi Pei ,&nbsp;Shuangyue Li ,&nbsp;Dong Chen ,&nbsp;Yanhan Zhou ,&nbsp;Xiaohong Du ,&nbsp;Xianxu Zhuang ,&nbsp;Haihui Zhuang ,&nbsp;Jiaojiao Yuan ,&nbsp;Juntao Zhang ,&nbsp;Xiaolin Xiong ,&nbsp;Peipei Ye ,&nbsp;Ying lu","doi":"10.1016/j.jcyt.2025.05.012","DOIUrl":"10.1016/j.jcyt.2025.05.012","url":null,"abstract":"<div><h3>Background</h3><div>Even with the tremendous progress made in treating multiple myeloma and lymphoma, autologous hematopoietic stem cell transplantation (ASCT) after high-dose chemotherapy is still an essential part of treatment. The mobilization of a sufficient number of high-quality peripheral blood stem cells (PBSC) is the main factor influencing the success of ASCT. However, further research is still needed to determine the best approach for hematopoietic stem cell mobilization.</div></div><div><h3>Study Design and Methods</h3><div>This retrospective, single-center study aimed to compare the efficacy and safety of hematopoietic stem cell mobilization between a combination regimen of etoposide, cytarabine, and pegfilgrastim (EAP) and granulocyte colony-stimulating factor (G-CSF) alone.</div></div><div><h3>Results</h3><div>The cohort comprised 52 patients assigned to the EAP mobilization protocol and 62 receiving G-CSF monotherapy. Compared with the G-CSF cohort, the EAP group demonstrated higher rates of prior exposure to multi-line chemotherapy (P=0.001), radiation therapy (P=0.018), and daratumumab therapy (P=0.006). Baseline demographic parameters showed no significant intergroup differences. The results indicated that EAP demonstrated superior efficacy in CD34⁺ cell yield optimization (P&lt;0.001) and apheresis session reduction (P&lt;0.001). However, this regimen was associated with increased infectious complications (P=0.003) and platelet transfusion requirements (P&lt;0.001). Conversely, G-CSF monotherapy necessitated greater plerixafor utilization (P&lt;0.001) and prolonged apheresis duration (P=0.002). Post-transplant hematological recovery analysis revealed accelerated platelet engraftment in the EAP cohort (P=0.037).</div></div><div><h3>Discussion</h3><div>The EAP regimen demonstrated significantly enhanced mobilization efficiency compared to the G-CSF monotherapy while maintaining an acceptable toxicity profile. These findings suggest that the EAP regimen may represent a superior alternative for mobilizing hematopoietic stem cells in patients with multiple myeloma or lymphoma.</div></div>","PeriodicalId":50597,"journal":{"name":"Cytotherapy","volume":"27 8","pages":"Pages 973-979"},"PeriodicalIF":3.7,"publicationDate":"2025-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144660963","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}