Spearheaded by the therapeutic use of chimeric antigen receptors (CARs) targeting CD19, synthetic immunology has entered the clinical arena. CARs are recombinant receptors for antigen that engage cell surface molecules through the variable region of an antibody and signal through arrayed T-cell activating and costimulatory domains. CARs allow redirection of T-cell cytotoxicity against any antigen of choice, independent of MHC expression. Patient T cells engineered to express CARs specific for CD19 have yielded remarkable outcomes in subjects with relapsed/refractory B- cell malignancies, setting off unprecedented interest in T-cell engineering and cell-based cancer immunotherapy. In this review, we present the challenges to extend the use of CAR T cells to solid tumors and other pathologies. We further highlight progress in CAR design, cell manufacturing, and genome editing, which in aggregate hold the promise of generating safer and more effective genetically instructed immunity. Novel engineered cell types, including innate T-cell types, natural killer (NK) cells, macrophages, and induced pluripotent stem cell-derived immune cells, are on the horizon, as are applications of CAR T cells to treat autoimmunity, severe infections, and senescence-associated pathologies.

中文翻译：

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CAR T 细胞：以 CD19 范式为基础

在靶向 CD19 的嵌合抗原受体 (CAR) 的治疗应用的引领下，合成免疫学已进入临床领域。CAR 是抗原的重组受体，它通过抗体的可变区与细胞表面分子结合，并通过排列的 T 细胞激活和共刺激结构域发出信号。CAR 允许针对任何选择的抗原重新定向 T 细胞的细胞毒性，而与 MHC 表达无关。经工程改造以表达 CD19 特异性 CAR 的患者 T 细胞在患有复发/难治性 B 细胞恶性肿瘤的受试者中取得了显着的成果，引发了对 T 细胞工程和基于细胞的癌症免疫治疗的前所未有的兴趣。在这篇综述中，我们提出了将 CAR T 细胞的使用扩展到实体瘤和其他疾病的挑战。我们进一步强调了 CAR 设计的进展，细胞制造和基因组编辑，它们总体上有望产生更安全、更有效的基因指导免疫。新的工程细胞类型，包括先天性 T 细胞类型、自然杀伤 (NK) 细胞、巨噬细胞和诱导多能干细胞衍生的免疫细胞，即将出现，CAR T 细胞在治疗自身免疫、严重感染、和衰老相关的病理。