{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T09:36:48Z","timestamp":1774949808239,"version":"3.50.1"},"reference-count":75,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,3,28]],"date-time":"2026-03-28T00:00:00Z","timestamp":1774656000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"EU Marie-Curie Doctoral Network\n              https:\/\/ror.org\/02aqv1x10","award":["10107286"],"award-info":[{"award-number":["10107286"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background\/Objectives: Point-of-care (PoC) manufactured fresh chimeric antigen receptor (CAR)-T cells are typically formulated in hypothermic preservation formulations (HPFs) and stored under hypothermic conditions (2\u20138 \u00b0C) until administered to the patient. However, in current HPFs the shelf life of fresh CAR-T cells is short (~24\u201336 h) due to limited CAR-T cell stability, which poses significant time constraints on manufacturing procedures and logistics. The objective of this study was to improve the stability and extend the shelf life of fresh clinical-grade CAR-T cell drug products (DPs). Methods: A novel HPF was developed by supplementing a base HPF with the novel excipient SUL-138, which stabilizes mitochondria during hypothermic storage and subsequent rewarming, alone or in combination with endogenous mitochondrial substrates. This panel of HPFs was first screened for their stability-improving characteristics in the model cell line Jurkat cells. Subsequently, HPFs were assessed for their stability-improving characteristics of clinical-grade CD19 CAR-T cell DPs. Critical quality attributes, including CAR-T cell viability, T-cell differentiation state, exhaustion markers, and functional potency were evaluated in a good manufacturing practice (GMP)-compliant stability study up to 72 h. Results: For Jurkat cells, HPFs supplemented with SUL-138 and a combination of glucose, glutamine, and succinate demonstrated the greatest stability improvement at 2\u20138 \u00b0C, improving cell viability from ~1% to &gt;85% after 72 h. For CAR-T cells, supplementation of HPFs with SUL-138 alone demonstrated the greatest improvement, resulting in a CAR-T cell viability from ~40% to &gt;85% after 72 h of storage at 2\u20138 \u00b0C, while no additional benefits from mitochondrial substrates were observed. The novel HPF did not significantly impact CAR-T cell potency test results, T cell subset distribution, or exhaustion markers compared to control. Conclusions: A novel clinical-grade HPF that significantly improved fresh CAR-T cell stability during hypothermic storage was developed. This novel HPF can aid in the establishment of GMP-compliant and PoC CAR-T cell manufacturing platforms.<\/jats:p>","DOI":"10.3390\/pharmaceutics18040414","type":"journal-article","created":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T13:41:03Z","timestamp":1774878063000},"page":"414","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Novel Hypothermic Preservation Formulation Containing SUL-138 Enables Long-Term Hypothermic Storage of Clinical-Grade CAR-T Cells"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4459-9532","authenticated-orcid":false,"given":"Aysenur","family":"\u00d6ner","sequence":"first","affiliation":[{"name":"Department of Hematology, University Medical Center Groningen (UMCG), Hanzeplein 1 (DA13), 9713 GZ Groningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-1597-6930","authenticated-orcid":false,"given":"Nina","family":"Nooteboom","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen (UMCG), Hanzeplein 1 (AP50), 9713 GZ Groningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linette","family":"Oosting","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen (UMCG), Hanzeplein 1 (AP50), 9713 GZ Groningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8358-765X","authenticated-orcid":false,"given":"Jos G. W.","family":"Kosterink","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen (UMCG), Hanzeplein 1 (AP50), 9713 GZ Groningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3308-0604","authenticated-orcid":false,"given":"Bart G. J.","family":"Dekkers","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen (UMCG), Hanzeplein 1 (AP50), 9713 GZ Groningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adrianus C.","family":"van der Graaf","sequence":"additional","affiliation":[{"name":"Sulfateq B.V., Admiraal de Ruyterlaan 5, 9726 GN Groningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5581-6950","authenticated-orcid":false,"given":"Tom van","family":"Meerten","sequence":"additional","affiliation":[{"name":"Department of Hematology, University Medical Center Groningen (UMCG), Hanzeplein 1 (DA13), 9713 GZ Groningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5850-5667","authenticated-orcid":false,"given":"Guido","family":"Krenning","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen (UMCG), Hanzeplein 1 (AP50), 9713 GZ Groningen, The Netherlands"},{"name":"Sulfateq B.V., Admiraal de Ruyterlaan 5, 9726 GN Groningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2691-8480","authenticated-orcid":false,"given":"Daniel H.","family":"Swart","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen (UMCG), Hanzeplein 1 (AP50), 9713 GZ Groningen, The Netherlands"},{"name":"Sulfateq B.V., Admiraal de Ruyterlaan 5, 9726 GN Groningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5133-2879","authenticated-orcid":false,"given":"Robin","family":"Dennebos","sequence":"additional","affiliation":[{"name":"Department of Hematology, University Medical Center Groningen (UMCG), Hanzeplein 1 (DA13), 9713 GZ Groningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Harm-Jan","family":"Lourens","sequence":"additional","affiliation":[{"name":"Department of Hematology, University Medical Center Groningen (UMCG), Hanzeplein 1 (DA13), 9713 GZ Groningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edwin","family":"Bremer","sequence":"additional","affiliation":[{"name":"Department of Hematology, University Medical Center Groningen (UMCG), Hanzeplein 1 (DA13), 9713 GZ Groningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8672-391X","authenticated-orcid":false,"given":"Bahez","family":"Gareb","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen (UMCG), Hanzeplein 1 (AP50), 9713 GZ Groningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4817","DOI":"10.1182\/blood-2011-04-348540","article-title":"Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias","volume":"118","author":"Brentjens","year":"2011","journal-title":"Blood"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1200\/JCO.2014.56.2025","article-title":"Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor","volume":"33","author":"Kochenderfer","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1040","DOI":"10.1056\/NEJMoa1504542","article-title":"Chimeric Antigen Receptor T Cells against CD19 for Multiple Myeloma","volume":"373","author":"Garfall","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"355ra116","DOI":"10.1126\/scitranslmed.aaf8621","article-title":"Immunotherapy of non-Hodgkin\u2019s lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells","volume":"8","author":"Turtle","year":"2016","journal-title":"Sci. Transl. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2980","DOI":"10.1182\/blood-2015-12-686725","article-title":"Phase 1 studies of central memory-derived CD19 CAR T-cell therapy following autologous HSCT in patients with B-cell NHL","volume":"127","author":"Wang","year":"2016","journal-title":"Blood"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1016\/S0140-6736(20)31366-0","article-title":"Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): A multicentre seamless design study","volume":"396","author":"Abramson","year":"2020","journal-title":"Lancet"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1016\/S0140-6736(21)00933-8","article-title":"Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): A phase 1b\/2 open-label study","volume":"398","author":"Berdeja","year":"2021","journal-title":"Lancet"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1038\/s41591-021-01622-0","article-title":"Tisagenlecleucel in adult relapsed or refractory follicular lymphoma: The phase 2 ELARA trial","volume":"28","author":"Fowler","year":"2022","journal-title":"Nat. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/S1470-2045(21)00591-X","article-title":"Axicabtagene ciloleucel in relapsed or refractory indolent non-Hodgkin lymphoma (ZUMA-5): A single-arm, multicentre, phase 2 trial","volume":"23","author":"Jacobson","year":"2022","journal-title":"Lancet Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2294","DOI":"10.1016\/S0140-6736(22)00662-6","article-title":"Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): Results from an interim analysis of an open-label, randomised, phase 3 trial","volume":"399","author":"Kamdar","year":"2022","journal-title":"Lancet"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1056\/NEJMoa2116133","article-title":"Axicabtagene Ciloleucel as Second-Line Therapy for Large B-Cell Lymphoma","volume":"386","author":"Locke","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1056\/NEJMoa1709866","article-title":"Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia","volume":"378","author":"Maude","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1056\/NEJMoa2024850","article-title":"Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma","volume":"384","author":"Munshi","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2531","DOI":"10.1056\/NEJMoa1707447","article-title":"Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma","volume":"377","author":"Neelapu","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1056\/NEJMoa1804980","article-title":"Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma","volume":"380","author":"Schuster","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1016\/S0140-6736(21)01222-8","article-title":"KTE-X19 for relapsed or refractory adult B-cell acute lymphoblastic leukaemia: Phase 2 results of the single-arm, open-label, multicentre ZUMA-3 study","volume":"398","author":"Shah","year":"2021","journal-title":"Lancet"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1331","DOI":"10.1056\/NEJMoa1914347","article-title":"KTE-X19 CAR T-Cell Therapy in Relapsed or Refractory Mantle-Cell Lymphoma","volume":"382","author":"Wang","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"137","DOI":"10.56875\/2589-0646.1048","article-title":"Chimeric Antigen Receptor Structure and Manufacturing of Clinical Grade CAR Engineered Cells using Different Bioreactors","volume":"15","author":"Syed","year":"2022","journal-title":"Hematol. Oncol. Stem Cell Ther."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1111\/bjh.17738","article-title":"The impact of bridging therapy prior to CD19-directed chimeric antigen receptor T-cell therapy in patients with large B-cell lymphoma","volume":"195","author":"Lutfi","year":"2021","journal-title":"Br. J. Haematol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Ortiz de Landazuri, I., Egri, N., Mu\u00f1oz-S\u00e1nchez, G., Ortiz-Maldonado, V., Bola\u00f1o, V., Guijarro, C., Pascal, M., and Juan, M. (2020). Manufacturing and Management of CAR T-Cell Therapy in \u2018COVID-19\u2019s Time\u2019: Central Versus Point of Care Proposals. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.573179"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1016\/j.jcyt.2020.08.007","article-title":"Comparison between centralized and decentralized supply chains of autologous chimeric antigen receptor T-cell therapies: A UK case study based on discrete event simulation","volume":"23","author":"Lam","year":"2021","journal-title":"Cytotherapy"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Van der Walle, C.F., Godbert, S., Saito, G., and Azhari, Z. (2021). Formulation Considerations for Autologous T Cell Drug Products. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13081317"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.actbio.2021.07.001","article-title":"Advanced biomaterials in cell preservation: Hypothermic preservation and cryopreservation","volume":"131","author":"Ma","year":"2021","journal-title":"Acta Biomater."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1007\/s10529-013-1349-5","article-title":"Low temperature cell pausing: An alternative short-term preservation method for use in cell therapies including stem cell applications","volume":"36","author":"Robinson","year":"2014","journal-title":"Biotechnol. Lett."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1089\/ten.tec.2011.0395","article-title":"Evaluation of bone marrow-derived mesenchymal stem cells after cryopreservation and hypothermic storage in clinically safe medium","volume":"18","author":"Ginis","year":"2012","journal-title":"Tissue Eng. Part C Methods"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1159\/000149797","article-title":"Hypothermic Injury: The Mitochondrial Calcium, ATP and ROS Love-Hate Triangle out of Balance","volume":"22","author":"Brinkkoetter","year":"2008","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1179\/his.2008.31.4.169","article-title":"The Effects of Storage Conditions on the Preservation of Enzymatic Activity in Bone","volume":"31","author":"Cosby","year":"2008","journal-title":"J. Histotechnol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1097\/01.tp.0000265586.66475.cc","article-title":"Perspectives in Organ Preservation","volume":"83","author":"Maathuis","year":"2007","journal-title":"Transplantation"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"59","DOI":"10.3727\/000000003783985160","article-title":"Induction of necrosis and DNA fragmentation during hypothermic preservation of hepatocytes in UW, HTK, and Celsior solutions","volume":"12","author":"Abrahamse","year":"2003","journal-title":"Cell Transplant."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1159\/000327033","article-title":"Organ Preservation: Current Concepts and New Strategies for the Next Decade","volume":"38","author":"Guibert","year":"2011","journal-title":"Transfus. Med. Hemother."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/S0011-2240(02)00104-9","article-title":"Acid\u2013base buffering in organ preservation solutions as a function of temperature: New parameters for comparing buffer capacity and efficiency","volume":"45","author":"Baicu","year":"2002","journal-title":"Cryobiology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.1126\/science.6298937","article-title":"Protons and Anaerobiosis","volume":"219","author":"Hochachka","year":"1983","journal-title":"Science"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1468","DOI":"10.1097\/00007890-199906150-00013","article-title":"Biphasic mechanism for hypothermic induced loss of protein synthesis in Hepatocytes1","volume":"67","author":"Vreugdenhil","year":"1999","journal-title":"Transplantation"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1093\/jb\/mvr030","article-title":"Differential function of protective agents at each stage of the hypothermic preservation of hepatocytes","volume":"149","author":"Dai","year":"2011","journal-title":"J. Biochem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"957054","DOI":"10.1155\/2013\/957054","article-title":"Oxidative Stress and Antioxidant Activity in Hypothermia and Rewarming: Can RONS Modulate the Beneficial Effects of Therapeutic Hypothermia?","volume":"2013","author":"Alva","year":"2013","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1089\/15383440260682071","article-title":"Improved Hypothermic Preservation of Human Renal Cells Through Suppression of Both Apoptosis and Necrosis","volume":"1","author":"Mathew","year":"2002","journal-title":"Cell Preserv. Technol."},{"key":"ref_37","first-page":"624","article-title":"Mitochondrial uncoupling prevents cold-induced oxidative stress: A case study using UCP1 knockout mice","volume":"217","author":"Stier","year":"2014","journal-title":"J. Exp. Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1563","DOI":"10.1016\/j.transproceed.2010.03.143","article-title":"Iron and Oxidative Stress in Cold-Initiated Necrotic Death of Rat Hepatocyte","volume":"42","author":"Niu","year":"2010","journal-title":"Transplant. Proc."},{"key":"ref_39","unstructured":"Sulfateq, B.V. (2025, July 31). Empowering Health. Available online: https:\/\/www.sulfateqbv.com."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2128","DOI":"10.1093\/ndt\/gfy080","article-title":"The 6-hydroxychromanol derivative SUL-109 ameliorates renal injury after deep hypothermia and rewarming in rats","volume":"33","author":"Vogelaar","year":"2018","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Star, B.S., van der Slikke, E.C., van Buiten, A., Henning, R.H., and Bouma, H.R. (2023). The Novel Compound SUL-138 Counteracts Endothelial Cell and Kidney Dysfunction in Sepsis by Preserving Mitochondrial Function. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24076330"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.biomaterials.2016.12.008","article-title":"The 6-chromanol derivate SUL-109 enables prolonged hypothermic storage of adipose tissue-derived stem cells","volume":"119","author":"Hajmousa","year":"2017","journal-title":"Biomaterials"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"106033","DOI":"10.1016\/j.ejps.2021.106033","article-title":"Towards prevention of ischemia-reperfusion kidney injury: Pre-clinical evaluation of 6-chromanol derivatives and the lead compound SUL-138","volume":"168","author":"Vogelaar","year":"2022","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1186\/s13195-022-01127-z","article-title":"The hibernation-derived compound SUL-138 shifts the mitochondrial proteome towards fatty acid metabolism and prevents cognitive decline and amyloid plaque formation in an Alzheimer\u2019s disease mouse model","volume":"14","author":"Koopmans","year":"2022","journal-title":"Alzheimer\u2019s Res. Ther."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1038\/s41467-019-13668-3","article-title":"Mitochondrial TCA cycle metabolites control physiology and disease","volume":"11","author":"Chandel","year":"2020","journal-title":"Nature Commun."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1496","DOI":"10.1038\/s12276-020-00504-8","article-title":"Glutamine reliance in cell metabolism","volume":"52","author":"Yoo","year":"2020","journal-title":"Exp. Mol. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.1016\/j.bbabio.2016.03.012","article-title":"Succinate, an intermediate in metabolism, signal transduction, ROS, hypoxia, and tumorigenesis","volume":"1857","author":"Tretter","year":"2016","journal-title":"Biochim. Biophys. Acta\u2013Bioenerg."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"jcs263653","DOI":"10.1242\/jcs.263653","article-title":"Pyruvate plus uridine augments mitochondrial respiration and prevents cardiac hypertrophy in zebrafish and H9c2 cells","volume":"138","author":"Mukherjee","year":"2025","journal-title":"J. Cell Sci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jcyt.2015.09.010","article-title":"Current perspectives on the use of ancillary materials for the manufacture of cellular therapies","volume":"18","author":"Solomon","year":"2015","journal-title":"Cytotherapy"},{"key":"ref_50","unstructured":"(2025, July 31). Miltenyi Biotec. CliniMACS\u00ae Formulation Solution. Available online: https:\/\/www.miltenyibiotec.com\/."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1038\/s41598-017-01149-w","article-title":"Succinate supplementation improves metabolic performance of mixed glial cell cultures with mitochondrial dysfunction","volume":"7","author":"Amaral","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"18910","DOI":"10.1038\/s41598-021-98082-w","article-title":"Role of pyruvate in maintaining cell viability and energy production under high-glucose conditions","volume":"11","author":"Yako","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"13432","DOI":"10.1038\/s41598-021-92959-6","article-title":"Glutamine supplementation stimulates cell proliferation in skeletal muscle and cultivated myogenic cells of low birth weight piglets","volume":"11","author":"Zhao","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1158\/2643-3230.BCD-23-0112","article-title":"Product Attributes of CAR T-cell Therapy Differentially Associate with Efficacy and Toxicity in Second-line Large B-cell Lymphoma (ZUMA-7)","volume":"5","author":"Filosto","year":"2023","journal-title":"Blood Cancer Discov."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1007\/s00262-023-03618-w","article-title":"A CAR-T response prediction model for r\/r B-NHL patients based on a T cell subset nomogram","volume":"73","author":"Zhang","year":"2024","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1038\/s41591-018-0010-1","article-title":"Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia","volume":"24","author":"Fraietta","year":"2018","journal-title":"Nat. Med."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1878","DOI":"10.1038\/s41591-020-1061-7","article-title":"Characteristics of anti-CD19 CAR T cell infusion products associated with efficacy and toxicity in patients with large B cell lymphomas","volume":"26","author":"Deng","year":"2020","journal-title":"Nat. Med."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"abj2820","DOI":"10.1126\/sciadv.abj2820","article-title":"Single-cell antigen-specific landscape of CAR T infusion product identifies determinants of CD19-positive relapse in patients with ALL","volume":"8","author":"Bai","year":"2022","journal-title":"Sci. Adv."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1016\/j.toxrep.2024.03.009","article-title":"Safety, tolerability and toxicokinetics of the novel mitochondrial drug SUL-138 administered orally to rat and minipig","volume":"12","author":"Swart","year":"2024","journal-title":"Toxicol. Rep."},{"key":"ref_60","first-page":"224","article-title":"Prediction of blood volume in normal human adults","volume":"51","author":"Nadler","year":"1962","journal-title":"Surgery"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"e100985","DOI":"10.1002\/alz70859_100985","article-title":"First-In-Human, Single Ascending Dose and Food-Effect Study in Healthy Volunteers of SUL-238, a Novel Orally Administered Mitochondria-Directed Drug Candidate","volume":"21","author":"Ulu","year":"2025","journal-title":"Alzheimers Dement."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1016\/j.bbmt.2019.12.770","article-title":"SUL-109 Protects Hematopoietic Stem Cells from Apoptosis Induced by Short-Term Hypothermic Preservation and Maintains Their Engraftment Potential","volume":"26","author":"Visser","year":"2020","journal-title":"Biol. Blood Marrow Transplant."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1038\/s41598-018-36788-0","article-title":"The (R)-enantiomer of the 6-chromanol derivate SUL-121 improves renal graft perfusion via antagonism of the \u03b11-adrenoceptor","volume":"9","author":"Nakladal","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1786","DOI":"10.1126\/science.aba1786","article-title":"Transient rest restores functionality in exhausted CAR-T cells through epigenetic remodeling","volume":"372","author":"Weber","year":"2021","journal-title":"Science"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"194","DOI":"10.5114\/ceji.2024.142116","article-title":"Transcriptome analysis of anaerobic glycolysis effects on Jurkat T cell proliferation","volume":"49","author":"Wang","year":"2024","journal-title":"Cent. Eur. J. Immunol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"10550","DOI":"10.1038\/s41598-017-10338-6","article-title":"A comprehensive characterization of the impact of mycophenolic acid on the metabolism of Jurkat T cells","volume":"7","author":"Poindessous","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"4941","DOI":"10.1074\/jbc.272.8.4941","article-title":"Effect of Extracellular AMP on Cell Proliferation and Metabolism of Breast Cancer Cell Lines with High and Low Glycolytic Rates","volume":"272","author":"Mazurek","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/S1074-7613(01)00205-9","article-title":"Signaling takes a breath\u2014New quantitative perspectives on bioenergetics and signal transduction","volume":"15","author":"Krauss","year":"2001","journal-title":"Immunity"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1016\/S1097-2765(00)00066-6","article-title":"In the absence of extrinsic signals, nutrient utilization by lymphocytes is insufficient to maintain either cell size or viability","volume":"6","author":"Rathmell","year":"2000","journal-title":"Mol. Cell"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/0014-4827(73)90561-2","article-title":"Changes in the carbohydrate metabolism of mitogenically stimulated human peripheral lymphocytes. II. Relative importance of glycolysis and oxidative phosphorylation on phytohaemagglutinin stimulation","volume":"77","author":"Roos","year":"1973","journal-title":"Exp. Cell Res."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"0963689721999617","DOI":"10.1177\/0963689721999617","article-title":"Cryopreservation: An Overview of Principles and Cell-Specific Considerations","volume":"30","author":"Whaley","year":"2021","journal-title":"Cell Transplant."},{"key":"ref_72","first-page":"e31564","article-title":"Cryopreservation: A Review Article","volume":"14","author":"Jaiswal","year":"2022","journal-title":"Cureus"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1662","DOI":"10.1089\/ten.2004.10.1662","article-title":"Cell preservation in reparative and regenerative medicine: Evolution of individualized solution composition","volume":"10","author":"Mathew","year":"2004","journal-title":"Tissue Eng."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"\u015acie\u017cy\u0144ska, A., Soszy\u0144ska, M., Szpak, P., Krze\u015bniak, N., Malejczyk, J., and Kalaszczy\u0144ska, I. (2021). Influence of Hypothermic Storage Fluids on Mesenchymal Stem Cell Stability: A Comprehensive Review and Personal Experience. Cells, 10.","DOI":"10.3390\/cells10051043"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1007\/s00204-009-0419-x","article-title":"Hypothermic storage of isolated human hepatocytes: A comparison between University of Wisconsin solution and a hypothermosol platform","volume":"83","author":"Ostrowska","year":"2009","journal-title":"Arch. Toxicol."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/4\/414\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T08:42:04Z","timestamp":1774946524000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/4\/414"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,28]]},"references-count":75,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["pharmaceutics18040414"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics18040414","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,28]]}}}