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Current challenges and emerging opportunities of CAR-T cell therapies.
Journal of Controlled Release ( IF 10.5 ) Pub Date : 2019-12-30 , DOI: 10.1016/j.jconrel.2019.12.047 Teresa R Abreu 1 , Nuno A Fonseca 2 , Nélio Gonçalves 3 , João Nuno Moreira 1
Journal of Controlled Release ( IF 10.5 ) Pub Date : 2019-12-30 , DOI: 10.1016/j.jconrel.2019.12.047 Teresa R Abreu 1 , Nuno A Fonseca 2 , Nélio Gonçalves 3 , João Nuno Moreira 1
Affiliation
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Infusion of chimeric antigen receptor (CAR)-genetically modified T cells (CAR-T cells) have led to remarkable clinical responses and cancer remission in patients suffering from relapsed or refractory B-cell malignancies. This is a new form of adoptive T cell therapy (ACT), whereby the artificial CAR enables the redirection of T cells endogenous antitumor activity towards a predefined tumor-associated antigen, leading to the elimination of a specific tumor. The early success in blood cancers has prompted the US Food and Drug Administration (FDA) to approve the first CAR-T cell therapies for the treatment of CD19-positive leukemias and lymphomas in 2017. Despite the emergence of CAR-T cells as one of the latest breakthroughs of cancer immunotherapies, their wider application has been hampered by specific life-threatening toxicities, and a substantial lack of efficacy in the treatment of solid tumors, owing to the strong immunosuppressive tumor microenvironment and the paucity of reliable tumor-specific targets. Herein, besides providing an overview of the emerging CAR-technologies and current clinical applications, the major hurdles of CAR-T cell therapies will be discussed, namely treatment-related life-threatening toxicities and the obstacles posed by the immunosupressive tumor-microenvironment of solid tumors, as well as the next-generation strategies currently designed to simultaneously improve safety and efficacy of CAR-T cell therapies in vivo.
中文翻译：
CAR-T细胞疗法的当前挑战和新兴机会。
嵌合抗原受体（CAR）基因修饰的T细胞（CAR-T细胞）的输注已导致患有复发性或难治性B细胞恶性肿瘤的患者发生显着的临床反应和癌症缓解。这是过继性T细胞疗法（ACT）的一种新形式，其中人工CAR可使T细胞内源性抗肿瘤活性重定向至预定的肿瘤相关抗原，从而消除特定的肿瘤。血液癌的早期成功促使美国食品药品监督管理局（FDA）于2017年批准了首个用于治疗CD19阳性白血病和淋巴瘤的CAR-T细胞疗法。癌症免疫疗法的最新突破，其广泛的应用受到威胁生命的特定毒性的阻碍，由于强大的免疫抑制性肿瘤微环境和缺乏可靠的肿瘤特异性靶标，因此在实体瘤的治疗中基本上缺乏疗效。在此，除了概述新兴的CAR技术和当前的临床应用外，还将讨论CAR-T细胞疗法的主要障碍，即与治疗相关的威胁生命的毒性以及固体免疫抑制性肿瘤微环境带来的障碍。肿瘤以及目前旨在同时提高体内CAR-T细胞疗法的安全性和功效的下一代策略。
更新日期：2019-12-30
中文翻译：
CAR-T细胞疗法的当前挑战和新兴机会。
嵌合抗原受体（CAR）基因修饰的T细胞（CAR-T细胞）的输注已导致患有复发性或难治性B细胞恶性肿瘤的患者发生显着的临床反应和癌症缓解。这是过继性T细胞疗法（ACT）的一种新形式，其中人工CAR可使T细胞内源性抗肿瘤活性重定向至预定的肿瘤相关抗原，从而消除特定的肿瘤。血液癌的早期成功促使美国食品药品监督管理局（FDA）于2017年批准了首个用于治疗CD19阳性白血病和淋巴瘤的CAR-T细胞疗法。癌症免疫疗法的最新突破，其广泛的应用受到威胁生命的特定毒性的阻碍，由于强大的免疫抑制性肿瘤微环境和缺乏可靠的肿瘤特异性靶标，因此在实体瘤的治疗中基本上缺乏疗效。在此，除了概述新兴的CAR技术和当前的临床应用外，还将讨论CAR-T细胞疗法的主要障碍，即与治疗相关的威胁生命的毒性以及固体免疫抑制性肿瘤微环境带来的障碍。肿瘤以及目前旨在同时提高体内CAR-T细胞疗法的安全性和功效的下一代策略。
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