Chimeric antigen receptor (CAR) T cell therapy has come of age, offering a potentially curative option for patients who are refractory to standard anti-cancer treatments. The success of CAR T cell therapy in the setting of acute lymphoblastic leukemia and specific types of B cell lymphoma led to rapid regulatory approvals of CD19-directed CAR T cells, first in the United States and subsequently across the globe. Despite these major milestones in the field of immuno-oncology, growing experience with CAR T cells has also highlighted the major limitations of this strategy, namely challenges associated with manufacturing a bespoke patient-specific product, intrinsic immune cell defects leading to poor CAR T cell function as well as persistence, and/or tumor cell resistance resulting from loss or modulation of the targeted antigen. In addition, both on- and off-tumor immunotoxicities and the financial burden inherent in conventional cellular biomanufacturing often hamper the success of CAR T cell-based treatment approaches. Herein, we provide an overview of the opportunities and challenges related to the first form of gene transfer therapy to gain commercial approval in the United States. Ongoing advances in the areas of genetic engineering, precision genome editing, toxicity mitigation methods and cell manufacturing will improve the efficacy and safety of CAR T cells for hematologic malignancies and expand the use of this novel class of therapeutics to reach solid tumors.

中文翻译：

---

临床实践：嵌合抗原受体 (CAR) T 细胞：抗击癌症的重大突破。

嵌合抗原受体 (CAR) T 细胞疗法已经成熟，为标准抗癌治疗无效的患者提供了潜在的治疗选择。CAR T 细胞疗法在治疗急性淋巴细胞白血病和特定类型的 B 细胞淋巴瘤方面取得成功，导致 CD19 导向的 CAR T 细胞获得快速监管批准，首先是在美国，随后在全球范围内。尽管在免疫肿瘤学领域取得了这些重大里程碑，但 CAR T 细胞的不断增长的经验也凸显了该策略的主要局限性，即与制造定制的患者特异性产品相关的挑战，内在免疫细胞缺陷导致 CAR T 细胞质量不佳功能以及持久性，和/或由靶向抗原的丢失或调节引起的肿瘤细胞抗性。此外，肿瘤内外的免疫毒性以及传统细胞生物制造固有的经济负担常常阻碍基于 CAR T 细胞的治疗方法的成功。在此，我们概述了与第一种基因转移疗法在美国获得商业批准相关的机遇和挑战。基因工程、精确基因组编辑、毒性缓解方法和细胞制造领域的持续进步将提高 CAR T 细胞治疗血液系统恶性肿瘤的疗效和安全性，并扩大这种新型疗法在实体肿瘤中的应用。我们概述了与在美国获得商业批准的第一种基因转移疗法相关的机遇和挑战。基因工程、精确基因组编辑、毒性缓解方法和细胞制造领域的持续进步将提高 CAR T 细胞治疗血液系统恶性肿瘤的疗效和安全性，并扩大这种新型疗法在实体肿瘤中的应用。我们概述了与在美国获得商业批准的第一种基因转移疗法相关的机遇和挑战。基因工程、精确基因组编辑、毒性缓解方法和细胞制造领域的持续进步将提高 CAR T 细胞治疗血液系统恶性肿瘤的疗效和安全性，并扩大这种新型疗法在实体肿瘤中的应用。