{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T20:46:10Z","timestamp":1791924370325,"version":"4.3.4"},"reference-count":42,"publisher":"Elsevier BV","issue":"8","license":[{"start":{"date-parts":[[2025,8,1]],"date-time":"2025-08-01T00:00:00Z","timestamp":1754006400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2025,8,1]],"date-time":"2025-08-01T00:00:00Z","timestamp":1754006400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2025,6,17]],"date-time":"2025-06-17T00:00:00Z","timestamp":1750118400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000038","name":"U.S. Food and Drug Administration","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000038","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006229","name":"Oak Ridge Institute for Science and Education","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006229","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000015","name":"U.S. Department of Energy","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000015","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["celltherapyjournal.org","clinicalkey.com","clinicalkey.com.au","clinicalkey.es","clinicalkey.fr","clinicalkey.jp","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Cytotherapy"],"published-print":{"date-parts":[[2025,8]]},"DOI":"10.1016\/j.jcyt.2025.05.008","type":"journal-article","created":{"date-parts":[[2025,5,22]],"date-time":"2025-05-22T12:03:32Z","timestamp":1747915412000},"page":"1013-1022","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":5,"title":["Feeder cell-free production of CAR-NK cells via activation of PKC and calcium signaling pathways"],"prefix":"10.1016","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8483-9940","authenticated-orcid":false,"given":"Supreet","family":"Khanal","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan","family":"Baer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1798-8863","authenticated-orcid":false,"given":"Nirjal","family":"Bhattarai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.jcyt.2025.05.008_bib0001","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2023.1166038","article-title":"Advancements in CAR-NK therapy: lessons to be learned from CAR-T therapy","volume":"14","author":"Kilgour","year":"2023","journal-title":"Front Immunol"},{"key":"10.1016\/j.jcyt.2025.05.008_bib0002","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2024.1519415","article-title":"Soluble factors released by peripheral blood-derived CAR-NK cells cause bystander myeloid cell activation","volume":"15","author":"Khanal","year":"2024","journal-title":"Front Immunol"},{"issue":"5","key":"10.1016\/j.jcyt.2025.05.008_bib0003","doi-asserted-by":"crossref","first-page":"e1507","DOI":"10.1002\/cti2.1507","article-title":"Optimisation of a primary human CAR-NK cell manufacturing pipeline","volume":"13","author":"Pfefferle","year":"2024","journal-title":"Clin Transl Immunology"},{"issue":"3","key":"10.1016\/j.jcyt.2025.05.008_bib0004","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1038\/s41573-019-0052-1","article-title":"NK cells for cancer immunotherapy","volume":"19","author":"Shimasaki","year":"2020","journal-title":"Nature reviews Drug discovery"},{"issue":"5","key":"10.1016\/j.jcyt.2025.05.008_bib0005","doi-asserted-by":"crossref","first-page":"e1507","DOI":"10.1002\/cti2.1507","article-title":"Optimisation of a primary human CAR-NK cell manufacturing pipeline","volume":"13","author":"Pfefferle","year":"2024","journal-title":"Clinical & Translational Immunology"},{"key":"10.1016\/j.jcyt.2025.05.008_bib0006","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.jim.2017.08.003","article-title":"Retroviral gene transfer into primary human NK cells activated by IL-2 and K562 feeder cells expressing membrane-bound IL-21","volume":"450","author":"Streltsova","year":"2017","journal-title":"J Immunol Methods"},{"key":"10.1016\/j.jcyt.2025.05.008_bib0007","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/ar2336","article-title":"The proinflammatory cytokines IL-2, IL-15 and IL-21 modulate the repertoire of mature human natural killer cell receptors","volume":"9","author":"De Rham","year":"2007","journal-title":"Arthritis research & therapy"},{"key":"10.1016\/j.jcyt.2025.05.008_bib0008","doi-asserted-by":"crossref","first-page":"2816","DOI":"10.3389\/fimmu.2019.02816","volume":"10","author":"Heinze","year":"2019","journal-title":"Frontiers in immunology"},{"issue":"9","key":"10.1016\/j.jcyt.2025.05.008_bib0009","doi-asserted-by":"crossref","first-page":"3897","DOI":"10.21873\/anticanres.16577","article-title":"Development of Genetically Engineered Feeder Cells for Natural Killer Cell Expansion","volume":"43","author":"Lee","year":"2023","journal-title":"Anticancer Res"},{"issue":"9","key":"10.1016\/j.jcyt.2025.05.008_bib0010","doi-asserted-by":"crossref","first-page":"3770","DOI":"10.1172\/JCI125916","article-title":"Chronic stimulation drives human NK cell dysfunction and epigenetic reprograming","volume":"129","author":"Merino","year":"2019","journal-title":"J Clin Invest"},{"issue":"4","key":"10.1016\/j.jcyt.2025.05.008_bib0011","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1038\/s41409-023-02180-4","article-title":"Manufacturing of primary CAR-NK cells in an automated system for the treatment of acute myeloid leukemia","volume":"59","author":"Albinger","year":"2024","journal-title":"Bone Marrow Transplant"},{"issue":"9","key":"10.1016\/j.jcyt.2025.05.008_bib0012","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1016\/j.tibtech.2014.06.007","article-title":"Towards efficient cancer immunotherapy: advances in developing artificial antigen-presenting cells","volume":"32","author":"Eggermont","year":"2014","journal-title":"Trends Biotechnol"},{"issue":"10","key":"10.1016\/j.jcyt.2025.05.008_bib0013","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0187123","article-title":"Src-family kinases negatively regulate NFAT signaling in resting human T cells","volume":"12","author":"Baer","year":"2017","journal-title":"PLoS One"},{"issue":"3","key":"10.1016\/j.jcyt.2025.05.008_bib0014","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1097\/CJI.0000000000000402","article-title":"TCR-independent Activation in Presence of a Src-family Kinase Inhibitor Improves CAR-T Cell Product Attributes","volume":"45","author":"Lamture","year":"2022","journal-title":"J Immunother"},{"issue":"4","key":"10.1016\/j.jcyt.2025.05.008_bib0015","doi-asserted-by":"crossref","first-page":"1283","DOI":"10.4049\/jimmunol.143.4.1283","article-title":"Mechanisms of T cell activation by the calcium ionophore ionomycin","volume":"143","author":"Chatila","year":"1989","journal-title":"J Immunol"},{"key":"10.1016\/j.jcyt.2025.05.008_bib0016","doi-asserted-by":"crossref","first-page":"1","DOI":"10.7554\/eLife.73282","article-title":"Inhibition of SHP-1 activity by PKC-theta regulates NK cell activation threshold and cytotoxicity","volume":"11","author":"Ben-Shmuel","year":"2022","journal-title":"Elife"},{"issue":"3","key":"10.1016\/j.jcyt.2025.05.008_bib0017","doi-asserted-by":"crossref","first-page":"e311","DOI":"10.1038\/emm.2017.42","article-title":"Molecular checkpoints controlling natural killer cell activation and their modulation for cancer immunotherapy","volume":"49","author":"Kwon","year":"2017","journal-title":"Exp Mol Med"},{"issue":"10","key":"10.1016\/j.jcyt.2025.05.008_bib0018","doi-asserted-by":"crossref","first-page":"4109","DOI":"10.1182\/blood-2008-02-139527","article-title":"NK cell-activating receptors require PKC-theta for sustained signaling, transcriptional activation, and IFN-gamma secretion","volume":"112","author":"Tassi","year":"2008","journal-title":"Blood"},{"issue":"2","key":"10.1016\/j.jcyt.2025.05.008_bib0019","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1038\/s41577-021-00547-6","article-title":"Cytokine release syndrome and associated neurotoxicity in cancer immunotherapy","volume":"22","author":"Morris","year":"2022","journal-title":"Nat Rev Immunol"},{"key":"10.1016\/j.jcyt.2025.05.008_bib0020","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2021.693016","article-title":"CAR-T Cell Therapy: Mechanism, Management, and Mitigation of Inflammatory Toxicities","volume":"12","author":"Fischer","year":"2021","journal-title":"Front Immunol"},{"issue":"4","key":"10.1016\/j.jcyt.2025.05.008_bib0021","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1111\/j.1365-2567.2007.02730.x","article-title":"Interleukin-21 activates human natural killer cells and modulates their surface receptor expression","volume":"123","author":"Skak","year":"2008","journal-title":"Immunology"},{"issue":"4","key":"10.1016\/j.jcyt.2025.05.008_bib0022","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1084\/jem.180.4.1395","article-title":"Interleukin (IL) 15 is a novel cytokine that activates human natural killer cells via components of the IL-2 receptor","volume":"180","author":"Carson","year":"1994","journal-title":"J Exp Med"},{"issue":"5813","key":"10.1016\/j.jcyt.2025.05.008_bib0023","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1038\/291335a0","article-title":"Interleukin-2 augments natural killer cell activity","volume":"291","author":"Henney","year":"1981","journal-title":"Nature"},{"issue":"1","key":"10.1016\/j.jcyt.2025.05.008_bib0024","article-title":"Efficient feeder cells preparation system for large-scale preparation and application of induced pluripotent stem cells","volume":"7","author":"Li","year":"2017","journal-title":"Sci Rep"},{"issue":"1","key":"10.1016\/j.jcyt.2025.05.008_bib0025","doi-asserted-by":"crossref","first-page":"117","DOI":"10.3390\/cancers15010117","article-title":"CAR-NK as a rapidly developed and efficient immunotherapeutic strategy against cancer","volume":"15","author":"W\u0142odarczyk","year":"2022","journal-title":"Cancers"},{"key":"10.1016\/j.jcyt.2025.05.008_bib0026","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ebiom.2020.102975","article-title":"CAR-NK cells: A promising cellular immunotherapy for cancer","volume":"59","author":"Xie","year":"2020","journal-title":"EBioMedicine"},{"key":"10.1016\/j.jcyt.2025.05.008_bib0027","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2021.707542","article-title":"CAR-NK cells: from natural basis to design for kill","volume":"12","author":"Khawar","year":"2021","journal-title":"Frontiers in immunology"},{"key":"10.1016\/j.jcyt.2025.05.008_bib0028","article-title":"Considerations for the Development of Chimeric Antigen Receptor (CAR) T Cell Products: Guidance for Industry","author":"Food","year":"2024","journal-title":"Docket Number: FDA-2021-D-0404"},{"key":"10.1016\/j.jcyt.2025.05.008_bib0029","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2022.802906","article-title":"Feeder cells at the interface of natural killer cell activation, expansion and gene editing","volume":"13","author":"Gurney","year":"2022","journal-title":"Frontiers in Immunology"},{"issue":"1","key":"10.1016\/j.jcyt.2025.05.008_bib0030","doi-asserted-by":"crossref","first-page":"ltac003","DOI":"10.1093\/immadv\/ltac003","article-title":"Engineering CAR-NK cells: how to tune innate killer cells for cancer immunotherapy","volume":"2","author":"Schmidt","year":"2022","journal-title":"Immunotherapy Advances"},{"key":"10.1016\/j.jcyt.2025.05.008_bib0031","article-title":"Preclinical and clinical studies of CAR-NK-cell therapies for malignancies","volume":"13","author":"Li","year":"2022","journal-title":"Frontiers in Immunology"},{"key":"10.1016\/j.jcyt.2025.05.008_bib0032","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13045-020-01014-w","article-title":"NK cell-based cancer immunotherapy: from basic biology to clinical development","volume":"14","author":"Liu","year":"2021","journal-title":"Journal of hematology & oncology"},{"key":"10.1016\/j.jcyt.2025.05.008_bib0033","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2015.00578","article-title":"The application of natural killer cell immunotherapy for the treatment of cancer","volume":"6","author":"Rezvani","year":"2015","journal-title":"Frontiers in immunology"},{"issue":"1","key":"10.1016\/j.jcyt.2025.05.008_bib0034","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1038\/cdd.2013.26","article-title":"Molecular mechanisms of natural killer cell activation in response to cellular stress","volume":"21","author":"Chan","year":"2014","journal-title":"Cell Death & Differentiation"},{"issue":"1","key":"10.1016\/j.jcyt.2025.05.008_bib0035","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.jcyt.2014.08.003","article-title":"Differential activation of cord blood and peripheral blood natural killer cells by cytokines","volume":"17","author":"Alnabhan","year":"2015","journal-title":"Cytotherapy"},{"issue":"1","key":"10.1016\/j.jcyt.2025.05.008_bib0036","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-018-29355-0","article-title":"Characterization of the effects of immunomodulatory drug fingolimod (FTY720) on human T cell receptor signaling pathways","volume":"8","author":"Baer","year":"2018","journal-title":"Scientific reports"},{"key":"10.1016\/j.jcyt.2025.05.008_bib0037","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/j.crimmu.2021.10.002","article-title":"Optimization of stimulation and staining conditions for intracellular cytokine staining (ICS) for determination of cytokine-producing T cells and monocytes","volume":"2","author":"Mandala","year":"2021","journal-title":"Current research in immunology"},{"key":"10.1016\/j.jcyt.2025.05.008_bib0038","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1016\/j.omtm.2021.01.008","article-title":"Systematic improvements in lentiviral transduction of primary human natural killer cells undergoing ex vivo expansion","volume":"20","author":"Allan","year":"2021","journal-title":"Mol Ther Methods Clin Dev"},{"key":"10.1016\/j.jcyt.2025.05.008_bib0039","doi-asserted-by":"crossref","first-page":"930","DOI":"10.3389\/fimmu.2017.00930","article-title":"Developmental and Functional Control of Natural Killer Cells by Cytokines","volume":"8","author":"Wu","year":"2017","journal-title":"Front Immunol"},{"issue":"7","key":"10.1016\/j.jcyt.2025.05.008_bib0040","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1016\/j.imbio.2015.01.009","article-title":"Multiple effects of IL-21 on human NK cells in ex vivo expansion","volume":"220","author":"Li","year":"2015","journal-title":"Immunobiology"},{"issue":"1","key":"10.1016\/j.jcyt.2025.05.008_bib0041","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-019-51287-6","article-title":"Membrane bound IL-21 based NK cell feeder cells drive robust expansion and metabolic activation of NK cells","volume":"9","author":"Ojo","year":"2019","journal-title":"Sci Rep"},{"issue":"9","key":"10.1016\/j.jcyt.2025.05.008_bib0042","doi-asserted-by":"crossref","first-page":"4010","DOI":"10.1158\/0008-5472.CAN-08-3712","article-title":"Expansion of highly cytotoxic human natural killer cells for cancer cell therapy","volume":"69","author":"Fujisaki","year":"2009","journal-title":"Cancer Res"}],"container-title":["Cytotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S1465324925007170?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S1465324925007170?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,7,25]],"date-time":"2025-07-25T23:36:04Z","timestamp":1753486564000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S1465324925007170"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8]]},"references-count":42,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2025,8]]}},"alternative-id":["S1465324925007170"],"URL":"https:\/\/doi.org\/10.1016\/j.jcyt.2025.05.008","relation":{},"ISSN":["1465-3249"],"issn-type":[{"value":"1465-3249","type":"print"}],"subject":[],"published":{"date-parts":[[2025,8]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Feeder cell-free production of CAR-NK cells via activation of PKC and calcium signaling pathways","name":"articletitle","label":"Article Title"},{"value":"Cytotherapy","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.jcyt.2025.05.008","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"Published by Elsevier Inc. on behalf of International Society for Cell & Gene Therapy.","name":"copyright","label":"Copyright"}]}}