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Nevertheless, over 40% of B cell malignancy patients experience a relapse after CAR-T therapy, likely due to inadequate persistence of the modified T cells in the body. IL15, known for its pro-survival and proliferative properties, has been suggested for incorporation into the fourth generation of CAR-T cells to enhance their persistence. However, the potential systemic toxicity associated with this cytokine warrants further evaluation.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We analyzed the persistence, antitumor efficacy and potential toxicity of anti-mouse CD19 CAR-T cells which express a membrane-bound IL15-IL15R\u03b1 chimeric protein (CD19\/mbIL15q CAR-T), in BALB\/c mice challenged with A20 tumor cells as well as in NSG mice.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Conventional CD19 CAR-T cells showed low persistence and poor efficacy in BALB\/c mice treated with mild lymphodepletion regimens (total body irradiation (TBI) of 1 Gy). CD19\/mbIL15q CAR-T exhibits prolonged persistence and enhanced in vivo efficacy, effectively eliminating established A20 B cell lymphoma. However, this CD19\/mbIL15q CAR-T displays important long-term toxicities, with marked splenomegaly, weight loss, transaminase elevations, and significant inflammatory findings in some tissues. Mice survival is highly compromised after CD19\/mbIL15q CAR-T cell transfer, particularly if a high TBI regimen is applied before CAR-T cell transfer.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Tethered IL15-IL15R\u03b1 augments the antitumor activity of CD19 CAR-T cells but displays long-term toxicity in immunocompetent mice. Inducible systems to regulate IL15-IL15R\u03b1 expression could be considered to control this toxicity.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jitc-2023-008572","type":"journal-article","created":{"date-parts":[[2024,7,2]],"date-time":"2024-07-02T01:26:05Z","timestamp":1719883565000},"page":"e008572","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":26,"title":["Tethered IL15-IL15R\u03b1 augments antitumor activity of CD19 CAR-T cells but displays long-term toxicity in an immunocompetent lymphoma mouse model"],"prefix":"10.1136","volume":"12","author":[{"given":"In\u00e9s","family":"S\u00e1nchez-Moreno","sequence":"first","affiliation":[{"name":"Immunology and Immunotherapy Program, Center for Applied Medical Research (CIMA), University of Navarra, IdISNA, Pamplona, 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