Roybal Kole T, Rupp Levi J, Morsut Leonardo, Walker Whitney J, McNally Krista A, Park Jason S, Lim Wendell A
Department of Cellular & Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Center for Systems and Synthetic Biology, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, San Francisco, CA 94158, USA.
Department of Cellular & Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Center for Systems and Synthetic Biology, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, San Francisco, CA 94158, USA.
Cell. 2016 Feb 11;164(4):770-9. doi: 10.1016/j.cell.2016.01.011. Epub 2016 Jan 28.
T cells can be re-directed to kill cancer cells using chimeric antigen receptors (CARs) or T cell receptors (TCRs). This approach, however, is constrained by the rarity of tumor-specific single antigens. Targeting antigens also found on bystander tissues can cause life-threatening adverse effects. A powerful way to enhance ON-target activity of therapeutic T cells is to engineer them to require combinatorial antigens. Here, we engineer a combinatorially activated T cell circuit in which a synthetic Notch receptor for one antigen induces the expression of a CAR for a second antigen. These dual-receptor AND-gate T cells are only armed and activated in the presence of dual antigen tumor cells. These T cells show precise therapeutic discrimination in vivo-sparing single antigen "bystander" tumors while efficiently clearing combinatorial antigen "disease" tumors. This type of precision dual-receptor circuit opens the door to immune recognition of a wider range of tumors. VIDEO ABSTRACT.
利用嵌合抗原受体（CAR）或T细胞受体（TCR），可使T细胞重新定向以杀死癌细胞。然而，这种方法受到肿瘤特异性单一抗原稀缺性的限制。靶向旁观者组织上也存在的抗原会导致危及生命的不良反应。增强治疗性T细胞靶向活性的一种有效方法是对其进行改造，使其需要组合抗原。在此，我们构建了一个组合激活的T细胞回路，其中针对一种抗原的合成Notch受体可诱导针对第二种抗原的CAR的表达。这些双受体“与”门T细胞仅在双抗原肿瘤细胞存在时才被武装并激活。这些T细胞在体内表现出精确的治疗区分能力——放过单一抗原的“旁观者”肿瘤，同时有效清除组合抗原的“疾病”肿瘤。这种精确的双受体回路为更广泛的肿瘤免疫识别打开了大门。视频摘要。
