Department of Dermatology, Friedrich-Alexander-University of Erlangen-Nürnberg (FAU), Universitätsklinikum Erlangen, Erlangen, Germany.
Department of Biology, Division of Genetics, Friedrich-Alexander-University of Erlangen-Nürnberg (FAU), Erlangen, Germany.
Exp Dermatol. 2018 Dec;27(12):1315-1321. doi: 10.1111/exd.13792.
Chimeric antigen receptor (CAR)-T cells are one of the impressive recent success stories of anti-cancer immunotherapy. Especially in haematological malignancies, this treatment strategy has shown promising results leading to the recent approval of two CAR-T cell constructs targeting CD19 in the United States and the European Union. After the huge success in haematological cancers, the next step will be the evaluation of its efficacy in different solid tumors, which is currently investigated in preclinical as well as clinical settings. A commonly examined tumor model in the context of immunotherapy is melanoma, since it is known for its immunogenic features. However, the first results of CAR-T cell therapy in solid tumors did not reveal the same impressive outcomes that were observed in haematological malignancies, as engineered cells need to cope with several challenges. Obstacles include the lack of migration of CAR-T cells from blood vessels to the tumor site as well as the immunosuppressive tumor microenvironment within solid tumors. Another hurdle is posed by the identification of an ideal target antigen to avoid on-target/off-tumor toxicities. Regarding immune escape mechanisms, which can be developed by tumor cells to bypass immune recognition, the observation of antigen loss should also be considered. This article gives an overview of the challenges displayed in CAR-T cell therapy for the use in solid tumors and discusses different new strategies and approaches that deal with these problems in order to improve CAR-T cell therapy, particularly for its use in melanoma.
嵌合抗原受体 (CAR)-T 细胞是癌症免疫疗法近期令人瞩目的成功案例之一。特别是在血液恶性肿瘤中，这种治疗策略已显示出有前景的结果，导致最近在美国和欧盟批准了两种针对 CD19 的 CAR-T 细胞构建体。在血液癌症中取得巨大成功之后，下一步将评估其在不同实体瘤中的疗效，目前正在临床前和临床环境中进行研究。在免疫疗法背景下，黑色素瘤是一个常见的肿瘤模型，因为它具有免疫原性特征。然而，CAR-T 细胞疗法在实体瘤中的初步结果并没有揭示出与血液恶性肿瘤中观察到的同样令人印象深刻的结果，因为工程化细胞需要应对几个挑战。障碍包括 CAR-T 细胞从血管迁移到肿瘤部位的缺乏以及实体瘤内的免疫抑制肿瘤微环境。另一个障碍是确定理想的靶抗原以避免靶内/靶外毒性。关于肿瘤细胞可以开发的免疫逃逸机制，以逃避免疫识别，也应该考虑抗原丢失的观察。本文概述了 CAR-T 细胞疗法在实体瘤中的应用所面临的挑战，并讨论了不同的新策略和方法，以解决这些问题，从而改善 CAR-T 细胞疗法，特别是在黑色素瘤中的应用。
