嵌合抗原受体
T细胞
CD19
CD28
CD38
细胞生物学
抗原
免疫疗法
生物
细胞毒性T细胞
CD8型
免疫学
医学
癌症研究
免疫系统
体外
干细胞
川地34
生物化学
作者
Afroditi Katsarou,Maria Sjöstrand,Jyoti Naik,Jorge Mansilla‐Soto,Dionysia Kefala,Georgios Kladis,Alexandros Nianias,Ruud Ruiter,Renée Poels,Irene Sarkar,Yash R. Patankar,Elena Merino,Rogier M. Reijmers,Kristine A. Frerichs,Huipin Yuan,Joost D. de Bruijn,Dina Stroopinsky,David Avigan,Niels W.C.J. van de Donk,Sonja Zweegman
标识
DOI:10.1126/scitranslmed.abh1962
摘要
Despite the high remission rates achieved using T cells bearing a chimeric antigen receptor (CAR) against hematogical malignancies, there is still a considerable proportion of patients who eventually experience tumor relapse. Clinical studies have established that mechanisms of treatment failure include the down-regulation of target antigen expression and the limited persistence of effective CAR T cells. We hypothesized that dual targeting mediated by a CAR and a chimeric costimulatory receptor (CCR) could simultaneously enhance T cell cytotoxicity and improve durability. Concomitant high-affinity engagement of a CD38-binding CCR enhanced the cytotoxicity of BCMA-CAR and CD19-CAR T cells by increasing their functional binding avidity. In comparison to second-generation BCMA-CAR or CD19-CAR T cells, double-targeted CAR + CD38-CCR T cells exhibited increased sensitivity to recognize and lyse tumor variants of multiple myeloma and acute lymphoblastic leukemia with low antigen density in vitro. In addition, complimentary costimulation by 4-1BB and CD28 endodomains provided by the CAR and CCR combination conferred increased cytokine secretion and expansion and improved persistence in vivo. The cumulatively improved properties of CAR + CCR T cells enabled the in vivo eradication of antigen-low tumor clones, which were otherwise resistant to treatment with conventional CAR T cells. Therefore, multiplexing targeting and costimulation through the combination of a CAR and a CCR is a powerful strategy to improve the clinical outcomes of CAR T cells by enhancing cytotoxic efficacy and persistence, thus preventing relapses of tumor clones with low target antigen density.
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