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While chimeric antigen receptor T cell (CART) immunotherapies have achieved remarkable remission rates in children with relapsed\/refractory B-ALL, ~50% of CD19CART-treated patients relapse again, many with CD19 antigen loss. We previously reported preclinical activity of thymic stromal lymphopoietin receptor-targeted cellular immunotherapy (TSLPRCART) against <jats:italic>CRLF2<\/jats:italic>-overexpressing ALL as an alternative approach. In this study, we posited that combinatorial TSLPRCART and ruxolitinib would have superior activity and first validated potent TSLPRCART-induced inhibition of leukemia proliferation in vitro in <jats:italic>CRLF2-<\/jats:italic>rearranged ALL cell lines and in vivo in Ph-like and DS-ALL patient-derived xenograft (PDX) models. However, simultaneous TSLPRCART\/ruxolitinib or CD19CART\/ruxolitinib treatment during initial CART expansion diminished T cell proliferation, blunted cytokine production, and\/or facilitated leukemia relapse, which was abrogated by time-sequenced\/delayed ruxolitinib co-exposure. Importantly, ruxolitinib co-administration prevented fatal TSLPRCART cytokine-associated toxicity in ALL PDX mice. Upon ruxolitinib withdrawal, TSLPRCART functionality recovered in vivo with clearance of subsequent ALL rechallenge. These translational studies demonstrate an effective two-pronged therapeutic strategy that mitigates acute CART-induced hyperinflammation and provides potential anti-leukemia \u2018maintenance\u2019 relapse prevention for <jats:italic>CRLF2<\/jats:italic>-rearranged Ph-like and DS-ALL.<\/jats:p>","DOI":"10.1038\/s41375-024-02493-3","type":"journal-article","created":{"date-parts":[[2024,12,16]],"date-time":"2024-12-16T07:15:22Z","timestamp":1734333322000},"page":"555-567","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Co-targeting of the thymic stromal lymphopoietin receptor to decrease immunotherapeutic resistance in CRLF2-rearranged Ph-like and Down syndrome acute lymphoblastic leukemia"],"prefix":"10.1038","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0225-9724","authenticated-orcid":false,"given":"Tommaso","family":"Balestra","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3608-7649","authenticated-orcid":false,"given":"Lisa M","family":"Niswander","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Asen","family":"Bagashev","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph P","family":"Loftus","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Savannah L","family":"Ross","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert K","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samantha M","family":"McClellan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2435-7739","authenticated-orcid":false,"given":"Jacob J","family":"Junco","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diego A","family":"B\u00e1rcenas L\u00f3pez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4081-8195","authenticated-orcid":false,"given":"Karen R.","family":"Rabin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8044-5226","authenticated-orcid":false,"given":"Terry J","family":"Fry","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1327-1662","authenticated-orcid":false,"given":"Sarah K","family":"Tasian","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,12,16]]},"reference":[{"key":"2493_CR1","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/S1470-2045(08)70339-5","volume":"10","author":"ML Den Boer","year":"2009","unstructured":"Den Boer ML, van Slegtenhorst M, De Menezes RX, Cheok MH, Buijs-Gladdines JG, Peters ST, et al. 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Transpl Cell Ther. 2023;29:438 e431\u2013438 e416.","journal-title":"Transpl Cell Ther"}],"container-title":["Leukemia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41375-024-02493-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41375-024-02493-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41375-024-02493-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,4]],"date-time":"2025-03-04T15:49:56Z","timestamp":1741103396000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41375-024-02493-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,16]]},"references-count":62,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2025,3]]}},"alternative-id":["2493"],"URL":"https:\/\/doi.org\/10.1038\/s41375-024-02493-3","relation":{},"ISSN":["0887-6924","1476-5551"],"issn-type":[{"value":"0887-6924","type":"print"},{"value":"1476-5551","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,16]]},"assertion":[{"value":"28 June 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 November 2024","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 November 2024","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 December 2024","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"AB is a current employee of Carisma Therapeutics. SLR is a current employee of Parexel International. KRR has received preclinical research support from Incyte Corporation. TJF was a prior part-time employee of and consultant for Sana Biotechnology. TJF is an inventor on patent US11834509B2 (\u2018Thymic stromal lymphopoietin receptor-specific chimeric antigen receptors and methods using same\u2019). SKT receives clinical research funding from Incyte Corporation for conduction of the Children\u2019s Oncology Group AALL1521 phase 2 clinical trial (NCT02723994). The remaining authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"Viably cryopreserved primary pediatric, adolescent, and young adult ALL specimens used to create PDX models for these studies were obtained from leukemia biorepositories of the Children\u2019s Oncology Group, Children\u2019s Hospital of Philadelphia (CHOP), or Texas Children\u2019s Hospital under institutional review board (IRB)-approved research protocols following obtainment of informed consent in accordance with the Declaration of Helsinki. Use of coded leukemia specimens without identifying patient health information in these studies was deemed non-human subjects research and exempt from further review by the CHOP IRB and ethics committee. All animal studies were conducted under an Institutional Animal Care and Use Committee-approved protocol at CHOP in accordance with all guidelines and regulations.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}]}}