Molecular Therapy-Methods & Clinical Development最新文献

{"title":"Comparison of NSG-Quad and MISTRG-6 humanized mice for modeling circulating and tumor-infiltrating human myeloid cells.","authors":"Anna Chen, Viktoria Knöbl, Oliver Walzer, Jana Hauser, Ines Neuwirth, Magdalena Frank, Nina Braun, Semina Duvnjak, Johannes Reisecker, Carmen Stecher, Alex Farr, Christine Brostjan, Dietmar Herndler-Brandstetter","doi":"10.1016/j.omtm.2025.101487","DOIUrl":"10.1016/j.omtm.2025.101487","url":null,"abstract":"<p><p>Humanized mice are valuable preclinical models for immuno-oncology research because they allow modeling of human immune cells and human tumors <i>in vivo</i>. Myeloid cells are highly abundant in many tumors and have been associated with tumor progression, metastasis, and therapy resistance. Next-generation humanized mice have been generated to improve the development, diversity, and function of human myeloid cells. In this study, we analyzed human immune cell development and myeloid cell composition in NSG-Quad and MISTRG-6 mice. NSG-Quad mice supported the development of tissue-resident and tumor-infiltrating human macrophages at levels almost comparable to those of MISTRG-6 mice. However, the development of human CD4⁺ and CD8⁺ T cells was impaired in the blood and spleen but not in the tumor of NSG-Quad mice. In a subset of NSG-Quad mice, human monocytes exhibited increased cellular granularity and elevated expression of activation and checkpoint molecules, consistent with a monocyte hyperactivation syndrome. Our study provides a comprehensive comparative analysis of the frequency and characteristics of circulating, tissue-resident, and tumor-infiltrating myeloid cell populations in NSG-Quad and MISTRG-6 mice, which is key to accurately design and interpret human tumor xenograft studies, particularly with regard to faithful reconstruction of the human tumor-immune microenvironment and preclinical testing.</p>","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":"33 2","pages":"101487"},"PeriodicalIF":4.6,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12152875/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144276652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anti-TNF-α antisense-oligonucleotide-conjugated PLG nanoparticles protect transplanted islets.","authors":"Elizabeth J Bealer, Namit Padgaonkar, Kelly Crumley, Eiji Saito, Zoe Beekman, Alexa DeKorte, Thazha P Prakash, Alexey Revenko, Lonnie D Shea","doi":"10.1016/j.omtm.2025.101489","DOIUrl":"10.1016/j.omtm.2025.101489","url":null,"abstract":"<p><p>One of the many challenges for islet transplantation as a treatment for type 1 diabetes is inflammation that contributes to islet de-differentiation and death. Innate immune cells such as monocytes and macrophages secrete tumor necrosis factor alpha (TNF-α), interleukin 1β (IL-1β), inducible nitric oxide synthase (iNOS), and IL-6, which directly contribute to islet dysfunction. Attenuation of the early inflammatory response post-transplantation may protect cell survival and subsequent function. Herein, we investigate the development of anti-TNF-α antisense-oligonucleotide-conjugated polylactide-co-glycolide nanoparticles (PLG-aTNF-α NPs) as an anti-inflammatory therapy after stem-cell-derived islet transplantation. PLG-aTNF-α NPs are shelf stable and successfully reduce TNF-α secretion and expression in inflammatory macrophages. Synergy between the aTNF-α antisense oligonucleotide and the polylactide-co-glycolide NPs results in further knockdown of IL-1β, IL-6, iNOS, and IL-12 <i>in vitro</i> indicating PLG-aTNF-α NPs may protect against the inflammatory cascade <i>in vivo</i>. In a diabetic mouse model, stem-cell-derived islets transplanted to the peritoneal fat were protected after treatment with PLG-aTNF-α NPs compared with PLG NPs alone. <i>Tnfα</i> and <i>I</i> <i>l</i> <i>1β</i> expression was reduced in mice treated with PLG-aTNF-α NPs, indicating inflammation was reduced after transplant. PLG-aTNF-α NPs reduce TNF-α and protect islets, supporting their potential use as a therapeutic in islet transplantation.</p>","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":"33 2","pages":"101489"},"PeriodicalIF":4.6,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12151673/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144267845","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of circular AAV cargos for targeted seamless insertion with large serine integrases.","authors":"Brett J G Estes, Nisha Gandhi, Jessica R Von Stetina, Dev Paudel, Angela X Nan, Parth Amin, Joshua Rose, Shuai Wu, Kangni Zheng, Yijun Zhang, Jesse C Cochrane, Jonathan D Finn, Jenny Xie","doi":"10.1016/j.omtm.2025.101490","DOIUrl":"10.1016/j.omtm.2025.101490","url":null,"abstract":"<p><p>Recent advancements in gene insertion have shifted from DNA-repair-dependent mechanisms to more precise approaches, enhancing safety and predictability for editing outcomes. Integrase-mediated programmable genomic integration (I-PGI) utilizes a DNA cargo to insert transgenes in a targeted, unidirectional manner. <i>In vivo</i>, where nuclear delivery of DNA is challenging, adeno-associated virus (AAV) can act as the cargo vector. Although I-PGI does not require DNA double-strand breaks (DSBs) for activity, linear cargo, like AAV, stimulates DNA end-joining activity after integration. To mitigate potential risks from DSBs, we developed two circular AAV cargos capable of seamless gene insertion in non-dividing cells. We first harnessed the orthogonal property of large serine integrases to produce circle-AAV (cAAV) from linear viral genomes in cells. cAAV demonstrated seamless cargo integration in primary human hepatocytes (PHHs) and robust DSB-free insertion structures <i>in vivo</i>. We then investigated the delivery of a packaged circular AAV cargo (AAV.AD), which eliminates the need for enzymatic manipulation in the cell. AAV.AD exhibited functional seamless gene insertion in PHHs and showed cargo efficacy <i>in vivo</i>. Together, these findings provide evidence of DSB-free programmable genomic integration using integrase and AAV cargo, addressing a previously unrecognized challenge in the field.</p>","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":"33 2","pages":"101490"},"PeriodicalIF":4.6,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12166831/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144303583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The clinical quality management system of advanced therapy medicinal products in the hospital setting: A scoping review.","authors":"Junnan Shi, Jinagya Yang, Yu Zheng, Phyllis Hio Hong Wong, Hao Hu, Carolina Oi Lam Ung","doi":"10.1016/j.omtm.2025.101485","DOIUrl":"10.1016/j.omtm.2025.101485","url":null,"abstract":"<p><p>Advanced therapy medicinal products (ATMPs) require rigorous quality management to mitigate risks associated with their development and use in hospitals. This study aimed to identify guidelines, standards of practice, and practical experiences in ATMPs quality management in hospital settings. An integrative scoping review under PRISMA guidelines retrieved 14 studies from four databases, 144 quality management guidelines and standards, and risk management reports for approved ATMPs from three government agencies and six organizations. Thirteen models or programs of quality management practices for ATMPs were identified across 25 hospital-based settings in six countries. Major aspects of ATMPs included clinical quality and translation, logistics management, hospital preparation, and patient care. Primary goals of ATMPs management within hospitals involved regulatory compliance and accreditation with national and regional requirements and implementing and maintaining the standardized operational practices. Four priority actions to enhance the quality of ATMPs management were as follows: (1) risk-based procedures and strategies; (2) strengthening of the skills and knowledge of healthcare professionals and technical staff; (3) validation and maintenance of qualified storage, manufacturing, and delivery facilities; and (4) support for a documentation system. In summary, understanding key components of ATMPs management offers valuable insights for developing an adaptive quality management ecosystem supporting clinical translation.</p>","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":"33 2","pages":"101485"},"PeriodicalIF":4.6,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12179598/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144477872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhancing titers of therapeutic lentiviral vectors using PKC agonists.","authors":"Charles Moore-Kelly, Rajesh Reddem, Ben M Alberts, Jordan Wright, Thomas Evans, Anurag Kulkarni, Nicholas G Clarkson, Daniel C Farley, Kyriacos A Mitrophanous, Rui André Saraiva Raposo","doi":"10.1016/j.omtm.2025.101484","DOIUrl":"10.1016/j.omtm.2025.101484","url":null,"abstract":"<p><p>Lentiviral vector (LV)-based therapies employ the molecular machinery of HIV-1 to stably integrate therapeutic genes into patient cells for long-term disease correction. However, suboptimal expression of LV components in HEK293T-based production systems can limit titers and hinder clinical product development. Here, we identify protein kinase C (PKC) agonists as robust enhancers of LV production. PKC activation resulted in rapid transcription of LV genomic RNA and accelerated vector particle release in a manner that complemented the use of the histone deacetylase (HDAC) inhibitor, sodium butyrate. Stimulation of HEK293T cells strongly upregulated AP-1 transcription factor subunits independently of nuclear factor κB (NF-κB) pathway activation. Application of PKC agonists in LV production resulted in a ∼3-fold improvement in the titer of a chimeric antigen receptor (CAR)-LV. Furthermore, a ∼9-fold increase in titer was achieved when this induction method was combined with co-expression of an LV RNA-targeted U1 snRNA enhancer. Importantly, LV produced using PKC agonists had comparable particle-to-infectivity ratios and preserved T cell transduction efficiency. These findings suggest that incorporating PKC agonists into commercial LV manufacturing could considerably reduce the cost per patient dose of new LV-based gene therapies.</p>","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":"33 2","pages":"101484"},"PeriodicalIF":4.6,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12146000/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144259414","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A method to validate viral copy-number assay involving a hybrid amplicon and duplex droplet digital PCR.","authors":"Raymond Wu, Frank Luh, Soo-Mi Kweon, Yun Yen","doi":"10.1016/j.omtm.2025.101483","DOIUrl":"10.1016/j.omtm.2025.101483","url":null,"abstract":"<p><p>Viral copy-number (VCN) assay is a powerful, effective method to quantify toxicity, cellular kinetics, and durability of virus-modified cell therapy products. The qualification and validation of assay requires reference control. Traditionally, plasmids and cell lines are used as reference controls, but development and qualification of those controls require considerable time and resources. We propose a reference synthetic DNA fragment containing amplicons of woodchuck hepatitis virus posttranscriptional regulatory element (<i>WPRE</i>) and ribonuclease P protein subunit p30 (<i>RPP30</i>), connected by HindIII restriction enzyme cutting site, as a useful tool to qualify and validate duplex droplet digital PCR (ddPCR) assays for VCN. Using this hybrid amplicon, we qualified the duplex WPRE/RPP30 ddPCR assay by determining range of quantification, precision, bias, and robustness of the assay. The varying amount of input DNA showed upper limit, lower limit, and linearity of the assay. Coefficient of variation (CV) and % recovery showed assay precision and accuracy, respectively. Furthermore, the hybrid amplicon was used to determine assay robustness with potential conditions of variability. The hybrid amplicon was a comparable alternative to cell reference standards for validating VCN assay. In conclusion, <i>WPRE-RPP30</i> hybrid amplicon can be used as a routine quality control measure to validate digital PCR assays.</p>","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":"33 2","pages":"101483"},"PeriodicalIF":4.6,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12229726/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144576962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A sensitive sample preparation pipeline for adventitious virus detection using Oxford Nanopore sequencing.","authors":"Emmanuel K Tsinda, Charles A Swofford, James P B Strutt, José Sangerman, Raeuf Roushangar, Alexander Li, Lara M Gomez, Aidan N Bousquet, Caleb Neufeld, Jacqueline M Wolfrum, Jongyoon Han, Rohan B H Williams, Anthony J Sinskey, Paul W Barone, Stacy L Springs","doi":"10.1016/j.omtm.2025.101478","DOIUrl":"10.1016/j.omtm.2025.101478","url":null,"abstract":"<p><p>Recent regulatory guidance now encourages the use of sequencing as an alternative adventitious agent testing assay to lengthy compendial <i>in vivo</i> assays used for cell line qualification. Most short-read sequencing assays, however, still require over a week to obtain a final test result since the sequencing must be completed before bioinformatic analysis can begin, which is still too long for some cell and gene therapy products that must be released as soon as possible to reach critically ill patients. Oxford Nanopore sequencing can address these issues, as it provides real-time basecalling and sequence alignment, which can reduce the overall assay time. Still, as with any sequencing platform, the abundance of background nucleic acid from the human or mammalian host can mask the signal from a low-level viral contaminant. To address this, we have developed a sensitive sample preparation workflow using concentration, nuclease treatment, and agnostic PCR methods to eliminate background signals and amplify viral contaminant reads, leading to a 3-log improvement in the limit of detection that is comparable to or better than short-read sequencing approaches. This approach will lead to more rapid and improved detection of viral contaminants in cell and gene therapy manufacturing.</p>","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":"33 2","pages":"101478"},"PeriodicalIF":4.6,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12229724/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144576963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring human plasma proteomic variations in mucolipidosis type IV.","authors":"Brendan R Tobin, Albert Misko, Victoria Miller-Browne, Madison Sangster, Yulia Grishchuk, Levi B Wood","doi":"10.1016/j.omtm.2025.101479","DOIUrl":"10.1016/j.omtm.2025.101479","url":null,"abstract":"<p><p>Mucolipidosis IV (MLIV) is an autosomal-recessive pediatric disease that leads to motor and cognitive deficits and loss of vision. It is caused by loss of function of the lysosomal channel transient receptor potential mucolipin-1, TRPML1, and is associated with an early brain phenotype consisting of glial reactivity, hypomyelination, and lysosomal abnormalities. Although the field is approaching the first translationally relevant therapy, we currently lack a molecular signature of disease that can be used to detect therapeutic efficacy. Here, we analyzed 7,322 proteins in the plasma proteome from 17 MLIV patients and 37 controls and compared protein profiles with clinical measures of disease severity (motor function, muscle tone, and age). We found a decrease in neuronal proteins and an increase in muscle proteins in MLIV, consistent with neuronal dysfunction and muscle pathology observed in patients. Reduced synaptic proteins (e.g., GABARAP) best correlated with disease severity. Comparing the MLIV plasma proteome to the brain proteome from the MLIV mouse model identified shared alterations in 45 proteins, including upregulated proteins related to lysosomal function (e.g., ACTN2, GLB1) and downregulated proteins related to myelination (e.g., TPPP3, CNTN2). These data indicate that peripheral blood plasma protein signatures mirror changes found in the MLIV brain.</p>","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":"33 2","pages":"101479"},"PeriodicalIF":4.6,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12141561/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144250871","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interlaboratory assessment of candidate reference materials for lentiviral vector copy number and integration site measurements.","authors":"Hua-Jun He, Zhiyong He, Steven P Lund, Laure Turner, Yongjun Fan, Yu Qiu, David C Corney, Boro Dropulic, Rimas Orentas, Oxana Slessareva, Priscilla Welch, Katie Dungca, Ellen Stelloo, Gabrielle Dijksteel, Harma Feitsma, Sana Ahmed-Seghir, Rostyslav Makarenko, Engin Altunlu, Daniëlle Steenmans, Jan Spanholtz, Monica Raimo, Shai Senderovich, Barbara S Paugh, Chieh-Yuan Li, Benjamin Schroeder, Alexandra S Whale, Dilek Yener, Carole A Foy, Shareef Nahas, Feng Tu, Michael Sheldon, Yan Ding, Jennifer Kandell, Uma Lakshmipathy, Jennifer H McDaniel, Justin M Zook, Sierra Miller, Samantha Maragh, Simona Patange, Mahir Mohiuddin, Alessandro Tona, Kenneth D Cole, Sheng Lin-Gibson","doi":"10.1016/j.omtm.2025.101472","DOIUrl":"10.1016/j.omtm.2025.101472","url":null,"abstract":"<p><p>While lentiviral vectors have played a critical role in the emergence of gene-modified cell therapies, safety concerns remain regarding potential insertional mutagenesis. Regulatory authorities strongly recommend risk assessment and management of vector copy numbers (VCNs), integration profiles, and integration sites in the lentivirus-based cell and gene therapy products. However, accurately measuring these parameters remains a significant challenge due to the lack of standardized methodologies and VCN reference materials (RMs). Toward this challenge, we conducted an interlaboratory study on NIST candidate RMs for VCN measurements. The candidate RMs comprise five human genomic DNA samples or fixed cells from clonal Jurkat cell lines with defined VCNs ranging from 0 to 4. All 12 study participants were able to identify the VCN in the five blinded samples using quantitative PCR (qPCR), digital PCR (dPCR), or next generation sequencing (NGS) assays. Consensus value of VCN and integration sites in these candidate RMs were achieved. The fixed clonal VCN cells were also used to evaluate an emerging imaging-based technology called molecular combing. This interlaboratory assessment demonstrated the utility, commutability, and suitability of the NIST VCN candidate RMs for quality assurance and improved confidence in VCN, integration profile, and integration site measurements.</p>","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":"33 2","pages":"101472"},"PeriodicalIF":4.6,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12229725/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144576964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Optimization of lentiviral delivery of barcoded anti-CD20 chimeric antigen receptors into rhesus macaque and human natural killer cells.","authors":"Taha B Hayal, Aman A Mulla, David S J Allan, Brynn B Duncan, Saanika Joshi, So Gun Hong, Rafet Basar, Katayoun Rezvani, Richard W Childs, Chuanfeng Wu, Cynthia E Dunbar","doi":"10.1016/j.omtm.2025.101473","DOIUrl":"10.1016/j.omtm.2025.101473","url":null,"abstract":"<p><p>Natural killer (NK) cells are pivotal in immunosurveillance and hold great potential for immunotherapy due to their ability to target malignant cells. Their low risk of causing graft-versus-host disease (GvHD) post-allogenic transplantation underscores their potential as an off-the shelf cellular therapy tool. Advances in genetic engineering focus on improving NK targeting, persistence, and fitness. However, NK cells pose challenges for lentiviral transduction, which are clinically relevant and safe. In this study, we identified Poloxamer 407 (P407) as a novel transduction enhancer for rhesus macaque (RM) and human NK cells. We found that P407 significantly improved transduction efficiency, achieving up to 60% in expanded RM NK cells, without compromising cell viability or functionality. Additionally, P407 facilitated the expression of anti-CD20 chimeric antigen receptors (CARs) with or without interleukin (IL)-15. In a xenograft mouse model, CAR-IL15 NK cells demonstrated superior anti-tumor activity, and maintained higher clonal diversity tracked by genetic barcoding compared to CAR-NK cells lacking IL-15 <i>in vivo</i>. Additionally, in human NK cells, P407 combined with the TBK1/IKKε inhibitor, BX795, further improved lentivirus-mediated transduction. This study is the first to engineer NK cells from a clinically relevant rhesus macaque model in an adaptive cell therapy context and highlights P407's potential as a transduction enhancer.</p>","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":"33 2","pages":"101473"},"PeriodicalIF":4.6,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12229723/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144576965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}