biostudies-literatureCao Xthe major special project on public health science and technology in Tianjinthe Science and Technology Project of Tianjin Municipal Health CommitteeTianjin Health Research ProjectTianjin Key Medical Discipline (Specialty) Construction Project325https://www.ebi.ac.uk/biostudies/studies/S-EPMC12553573biostudies-literatureUnknown25(1)The efficacy of CD19 CAR-T cells in B-cell lymphoma patients is not as good as that in B-cell acute lymphoblastic leukemia (B-ALL) patients. This might be attributed to the intricate tumor microenvironment of B-cell lymphoma, which leads to CAR-T cell exhaustion, inability to sustain function, and difficulty infiltrating into the tumor interior. We developed CD19 CAR structures that simultaneously produce membrane-bound IL-15 (mbIL-15) and CXCR5. This design aims to enhance the migration of CAR-T cells into CXCL13+ B-cell lymphomas and their long-term antitumor ability. Compared with CD19 CAR-T cells, CD19 mbIL15-CXCR5 CAR-T cells exhibited greater cytotoxicity against CD19+ tumor cell lines in vitro. In particular, when exposed to recurrent tumor antigen stimulation, CD19 mbIL15-CXCR5 CARClinical and experimental medicineA novel fourth generation of CAR-T cells: CD19 CAR-T cells engineered to express membrane-bound interleukin-15 and CXCR5 for the treatment of lymphoma.PMC1255357324ZXGZSY00120TJYXZDXK-056BTJWJ2024QN040TJWJ2022XK018Liu JZhao MCao XSun RZhang YZhang XZhang MGuo SGuo RZhao YfalseA novel fourth generation of CAR-T cells: CD19 CAR-T cells engineered to express membrane-bound interleukin-15 and CXCR5 for the treatment of lymphoma.The efficacy of CD19 CAR-T cells in B-cell lymphoma patients is not as good as that in B-cell acute lymphoblastic leukemia (B-ALL) patients. This might be attributed to the intricate tumor microenvironment of B-cell lymphoma, which leads to CAR-T cell exhaustion, inability to sustain function, and difficulty infiltrating into the tumor interior. We developed CD19 CAR structures that simultaneously produce membrane-bound IL-15 (mbIL-15) and CXCR5. This design aims to enhance the migration of CAR-T cells into CXCL13+ B-cell lymphomas and their long-term antitumor ability. Compared with CD19 CAR-T cells, CD19 mbIL15-CXCR5 CAR-T cells exhibited greater cytotoxicity against CD19+ tumor cell lines in vitro. In particular, when exposed to recurrent tumor antigen stimulation, CD19 mbIL15-CXCR5 CAR2025-01-01T00:00:00Z2025 Oct2026-05-23T03:20:25.056Z2026-05-23T03:10:47.832ZS-EPMC125535734113793610.1007/s10238-025-01860-3