{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T05:26:33Z","timestamp":1783056393204,"version":"3.54.6"},"reference-count":63,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,5,9]],"date-time":"2025-05-09T00:00:00Z","timestamp":1746748800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Chimeric antigen receptor (CAR) T-cell therapies have achieved remarkable success in treating B-cell malignancies, including acute lymphoblastic leukemia (B-ALL). However, despite high remission rates, relapse due to antigen escape remains a significant challenge. To overcome this, designing CAR T-cells targeting multiple cancer antigens simultaneously is a promising strategy. NKG2D ligands (NKG2DL) are eight stress-induced ligands expressed by cancer cells but largely absent on healthy cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and Results<\/jats:title><jats:p>We hypothesized that simultaneous targeting of NKG2DL (using the NKG2D extracellular domain) and CD19 can prevent CD19 antigen escape and improve long-term remission rates in B-ALL patients. We developed three tandem CARs targeting both CD19 and NKG2DL and demonstrated that two tandem candidates were highly effective against both CD19+ and CD19- cancer cell lines. Importantly, when compared to CD19 CAR T-cells, tandem CAR T-cells exhibited comparable cytokine secretion, cytolytic activity and proliferation levels when incubated with cancer cells expressing CD19 and were still effective when incubated with cancer cells lacking CD19. Moreover, T-cells transduced with the selected CD19\/NKG2DL tandem CAR were functional against CD19+ primary B-ALL samples and controlled tumor growth in a highly challenging xenograft model representing a CD19- B-ALL relapse.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>These findings provide proof-of-concept that NKG2D-based tandem CARs offer a promising approach to overcome antigen escape and enhance anti-tumor efficacy in B-cell malignancies.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1557405","type":"journal-article","created":{"date-parts":[[2025,5,9]],"date-time":"2025-05-09T05:30:00Z","timestamp":1746768600000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["Tandem CAR T-cells targeting CD19 and NKG2DL can overcome CD19 antigen escape in 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