{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T21:39:38Z","timestamp":1790631578337,"version":"4.1.0"},"reference-count":19,"publisher":"Springer Science and Business Media LLC","issue":"9","license":[{"start":{"date-parts":[[2024,7,2]],"date-time":"2024-07-02T00:00:00Z","timestamp":1719878400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,7,2]],"date-time":"2024-07-02T00:00:00Z","timestamp":1719878400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Karolinska Institutet foundation","award":["2020-01402"],"award-info":[{"award-number":["2020-01402"]}]},{"DOI":"10.13039\/501100002794","name":"Cancerfonden","doi-asserted-by":"publisher","award":["19 0359 Pj"],"award-info":[{"award-number":["19 0359 Pj"]}],"id":[{"id":"10.13039\/501100002794","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002794","name":"Cancerfonden","doi-asserted-by":"publisher","award":["19 0002 FE"],"award-info":[{"award-number":["19 0002 FE"]}],"id":[{"id":"10.13039\/501100002794","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Cancer Society in Stockholm Research","award":["191222"],"award-info":[{"award-number":["191222"]}]},{"name":"Cancer Society in Stockholm Research","award":["221253"],"award-info":[{"award-number":["221253"]}]},{"DOI":"10.13039\/501100004047","name":"Karolinska Institute","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004047","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cancer Immunol Immunother"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>In addition to their immunosuppressive effect, cytostatics conditioning prior to adoptive therapy such as chimeric antigen receptor (CAR) T cells may play a role in debulking and remodeling the tumor microenvironment. We investigated in vitro the killing efficacy and impact of treosulfan and fludarabine on ovarian cancer cells expressing mesothelin (MSLN) and effect on MSLN-targeting CAR T cells. Treosulfan and fludarabine had a synergetic effect on killing of SKOV3 and OVCAR4 cells. Sensitivity to the combination of treosulfan and fludarabine was increased when SKOV3 cells expressed MSLN and when OVCAR4 cells were tested in hypoxia, while MSLN cells surface expression by SKOV3 and OVCAR4 cells was not altered after treosulfan or fludarabine exposure. Exposure to treosulfan or fludarabine (10\u00a0\u00b5M) neither impacted MSLN-CAR T cells degranulation, cytokines production upon challenge with MSLN\u2009+\u2009OVCAR3 cells, nor induced mitochondrial defects. Combination of treosulfan and fludarabine decreased MSLN-CAR T cells anti-tumor killing in normoxia but not hypoxia. In conclusion, treosulfan and fludarabine killed MSLN\u2009+\u2009ovarian cancer cells without altering MSLN-CAR T cells functions (at low cytostatics concentration) even in hypoxic conditions, and our data support the use of treosulfan and fludarabine as conditioning drugs prior to MSLN-CAR T cell therapy.<\/jats:p>","DOI":"10.1007\/s00262-024-03740-3","type":"journal-article","created":{"date-parts":[[2024,7,2]],"date-time":"2024-07-02T13:02:19Z","timestamp":1719925339000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Impact of fludarabine and treosulfan on ovarian tumor cells and mesothelin chimeric antigen receptor T cells"],"prefix":"10.1007","volume":"73","author":[{"given":"Ibrahim","family":"El-Serafi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabella","family":"Micallef Nilsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alina","family":"Moter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhe","family":"Duan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonas","family":"Mattsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Magalhaes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,7,2]]},"reference":[{"key":"3740_CR1","doi-asserted-by":"publisher","first-page":"S20","DOI":"10.1097\/IGC.0000000000001118","volume":"27","author":"J Chien","year":"2017","unstructured":"Chien J, Poole EM (2017) Ovarian cancer prevention, screening, and early detection: report from the 11th biennial ovarian cancer research symposium. Int J Gynecol Cancer 27:S20\u2013S22","journal-title":"Int J Gynecol Cancer"},{"issue":"2","key":"3740_CR2","doi-asserted-by":"publisher","first-page":"459","DOI":"10.4049\/jimmunol.1701155","volume":"200","author":"S Srivastava","year":"2018","unstructured":"Srivastava S, Riddell SR (2018) chimeric antigen receptor T cell therapy: challenges to bench-to-bedside efficacy. J Immunol 200(2):459\u2013468","journal-title":"J Immunol"},{"issue":"2","key":"3740_CR3","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1158\/2159-8290.CD-15-0583","volume":"6","author":"A Morello","year":"2016","unstructured":"Morello A, Sadelain M, Adusumilli PS (2016) Mesothelin-targeted cars: driving T cells to solid tumors. Cancer Discov 6(2):133\u2013146","journal-title":"Cancer Discov"},{"key":"3740_CR4","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1016\/j.canlet.2018.03.032","volume":"425","author":"YL Chen","year":"2018","unstructured":"Chen YL, Chang MC, Chiang YC, Lin HW, Sun NY, Chen CA et al (2018) Immuno-modulators enhance antigen-specific immunity and anti-tumor effects of mesothelin-specific chimeric DNA vaccine through promoting DC maturation. Cancer Lett 425:152\u2013163","journal-title":"Cancer Lett"},{"issue":"3","key":"3740_CR5","doi-asserted-by":"publisher","first-page":"542","DOI":"10.1038\/mt.2012.233","volume":"21","author":"TH Kang","year":"2013","unstructured":"Kang TH, Ma B, Wang C, Wu TC, Hung CF (2013) Targeted coating with antigenic peptide renders tumor cells susceptible to CD8(+) T cell-mediated killing. Mol Ther 21(3):542\u2013553","journal-title":"Mol Ther"},{"issue":"1","key":"3740_CR6","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1002\/stem.2715","volume":"36","author":"MD Jain","year":"2018","unstructured":"Jain MD, Davila ML (2018) Concise review: emerging principles from the clinical application of chimeric antigen receptor T cell therapies for B cell malignancies. Stem Cells 36(1):36\u201344","journal-title":"Stem Cells"},{"issue":"1","key":"3740_CR7","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1186\/s40425-018-0460-5","volume":"6","author":"MM Boyiadzis","year":"2018","unstructured":"Boyiadzis MM, Dhodapkar MV, Brentjens RJ, Kochenderfer JN, Neelapu SS, Maus MV et al (2018) Chimeric antigen receptor (CAR) T therapies for the treatment of hematologic malignancies: clinical perspective and significance. J Immunother Cancer 6(1):137","journal-title":"J Immunother Cancer"},{"issue":"2","key":"3740_CR8","first-page":"2063","volume":"16","author":"J Xu","year":"2018","unstructured":"Xu J, Wang Y, Shi J, Liu J, Li Q, Chen L (2018) Combination therapy: a feasibility strategy for CAR-T cell therapy in the treatment of solid tumors. Oncol Lett 16(2):2063\u20132070","journal-title":"Oncol Lett"},{"issue":"3","key":"3740_CR9","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1007\/s40265-017-0690-8","volume":"77","author":"KA Hay","year":"2017","unstructured":"Hay KA, Turtle CJ (2017) Chimeric antigen receptor (CAR) T cells: lessons learned from targeting of CD19 in B-cell malignancies. Drugs 77(3):237\u2013245","journal-title":"Drugs"},{"issue":"12","key":"3740_CR10","first-page":"6869","volume":"35","author":"R Chekerov","year":"2015","unstructured":"Chekerov R, Kaltenecker G, Reichert D, Gohler T, Klare P, Oskay-Ozcelik G et al (2015) Treosulfan in the treatment of advanced ovarian cancer-results of a German multicenter non-interventional study. Anticancer Res 35(12):6869\u20136875","journal-title":"Anticancer Res"},{"issue":"3","key":"3740_CR11","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1517\/17425255.2013.737319","volume":"9","author":"A Galaup","year":"2013","unstructured":"Galaup A, Paci A (2013) Pharmacology of dimethanesulfonate alkylating agents: busulfan and treosulfan. Expert Opin Drug Metab Toxicol 9(3):333\u2013347","journal-title":"Expert Opin Drug Metab Toxicol"},{"issue":"2","key":"3740_CR12","doi-asserted-by":"publisher","first-page":"725","DOI":"10.1182\/blood-2002-11-3615","volume":"103","author":"J Casper","year":"2004","unstructured":"Casper J, Knauf W, Kiefer T, Wolff D, Steiner B, Hammer U et al (2004) Treosulfan and fludarabine: a new toxicity-reduced conditioning regimen for allogeneic hematopoietic stem cell transplantation. Blood 103(2):725\u2013731","journal-title":"Blood"},{"issue":"4","key":"3740_CR13","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1007\/s12185-017-2320-3","volume":"106","author":"M Remberger","year":"2017","unstructured":"Remberger M, Torlen J, Serafi IE, Garming-Legert K, Bjorklund A, Ljungman P et al (2017) Toxicological effects of fludarabine and treosulfan conditioning before allogeneic stem-cell transplantation. Int J Hematol 106(4):471\u2013475","journal-title":"Int J Hematol"},{"issue":"5","key":"3740_CR14","doi-asserted-by":"publisher","first-page":"639","DOI":"10.1080\/10837450.2018.1551903","volume":"24","author":"I El-Serafi","year":"2019","unstructured":"El-Serafi I, Loy O, Zhao Y, Oerther S, Mattsson J (2019) Pre-formulation investigations for establishing a protocol for treosulfan handling and activation. Pharm Dev Technol 24(5):639\u2013648","journal-title":"Pharm Dev Technol"},{"issue":"2","key":"3740_CR15","doi-asserted-by":"publisher","first-page":"e005691","DOI":"10.1136\/jitc-2022-005691","volume":"11","author":"E Schoutrop","year":"2023","unstructured":"Schoutrop E, Poiret T, El-Serafi I, Zhao Y, He R, Moter A et al (2023) Tuned activation of MSLN-CAR T cells induces superior antitumor responses in ovarian cancer models. J Immunother Cancer 11(2):e005691","journal-title":"J Immunother Cancer"},{"issue":"2","key":"3740_CR16","doi-asserted-by":"publisher","first-page":"276","DOI":"10.2174\/1871520611313020014","volume":"13","author":"Z Tang","year":"2013","unstructured":"Tang Z, Qian M, Ho M (2013) The role of mesothelin in tumor progression and targeted therapy. Anticancer Agents Med Chem 13(2):276\u2013280","journal-title":"Anticancer Agents Med Chem"},{"key":"3740_CR17","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1186\/1476-4598-10-106","volume":"10","author":"U Bharadwaj","year":"2011","unstructured":"Bharadwaj U, Marin-Muller C, Li M, Chen C, Yao Q (2011) Mesothelin confers pancreatic cancer cell resistance to TNF-alpha-induced apoptosis through Akt\/PI3K\/NF-kappaB activation and IL-6\/Mcl-1 overexpression. Mol Cancer 10:106","journal-title":"Mol Cancer"},{"key":"3740_CR18","doi-asserted-by":"crossref","unstructured":"Mohty M, Minnema MC (2022) In: Kroger N, Gribben J, Chabannon C, Yakoub-Agha I, Einsele H (eds) The EBMT\/EHA CAR-T cell handbook, Cham, pp 131\u2013133","DOI":"10.1007\/978-3-030-94353-0_25"},{"issue":"1","key":"3740_CR19","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1007\/s00262-010-0920-3","volume":"60","author":"FJ Gassner","year":"2011","unstructured":"Gassner FJ, Weiss L, Geisberger R, Hofbauer JP, Egle A, Hartmann TN et al (2011) Fludarabine modulates composition and function of the T cell pool in patients with chronic lymphocytic leukaemia. Cancer Immunol Immunother 60(1):75\u201385","journal-title":"Cancer Immunol Immunother"}],"updated-by":[{"DOI":"10.1007\/s00262-024-03813-3","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2024,9,5]],"date-time":"2024-09-05T00:00:00Z","timestamp":1725494400000}}],"container-title":["Cancer Immunology, Immunotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00262-024-03740-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00262-024-03740-3\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00262-024-03740-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,5]],"date-time":"2024-09-05T09:12:57Z","timestamp":1725527577000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00262-024-03740-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,2]]},"references-count":19,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2024,9]]}},"alternative-id":["3740"],"URL":"https:\/\/doi.org\/10.1007\/s00262-024-03740-3","relation":{"correction":[{"id-type":"doi","id":"10.1007\/s00262-024-03813-3","asserted-by":"object"}]},"ISSN":["1432-0851"],"issn-type":[{"value":"1432-0851","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,2]]},"assertion":[{"value":"23 October 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 May 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 July 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 September 2024","order":4,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Correction","order":5,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"A Correction to this paper has been published:","order":6,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"https:\/\/doi.org\/10.1007\/s00262-024-03813-3","URL":"https:\/\/doi.org\/10.1007\/s00262-024-03813-3","order":7,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declared no conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}],"article-number":"163"}}