肿瘤细胞治疗研究
英文原题：Current and future perspectives of chimeric antigen receptors against glioblastoma.
最后，我们讨论了串联 CAR 和 synNotch CAR 在靶向多种 GBM 抗原时的优势。
多形性胶质母细胞瘤（GBM）是中枢神经系统恶性程度最高的肿瘤，即使接受治疗，5年生存率也仅为7.2%。表达嵌合抗原受体（CAR）的T细胞过继转移（ACT）治疗白血病和多发性骨髓瘤等血液系统恶性肿瘤已取得显著成功。然而，CAR-T治疗实体瘤，尤其是GBM，仍面临诸多挑战，阻碍其广泛应用。本文首先概述ACT治疗GBM的障碍，包括靶向肿瘤同时误伤正常组织的毒性、抗原调节、肿瘤异质性和免疫抑制性肿瘤微环境。随后介绍靶向特征明确GBM抗原的近期临床前及临床研究，包括白细胞介素13受体α2和表皮生长因子受体。文章还探讨GBM的其他靶点，包括研究较少的B7-H3（CD276）、碳酸酐酶IX和GD2神经节苷脂，以及CD70和NK 细胞2族成员D（NKG2D）配体。最后，本文介绍新型CAR结构带来的可能性，尤其是利用装甲型CAR改善CAR-T细胞存活和增殖，并讨论在同时靶向多种GBM抗原时串联CAR和synNotch CAR的优势。
Glioblastoma multiforme (GBM) is the most malignant form of cancer in the central nervous system; even with treatment, it has a 5-year survival rate of 7.2%. The adoptive cell transfer (ACT) of T cells expressing chimeric antigen receptors (CARs) has shown a remarkable success against hematological malignancies, namely leukemia and multiple myeloma. However, CAR T cell therapy against solid tumors, and more specifically GBM, is still riddled with challenges preventing its widespread adoption. Here, we first establish the obstacles in ACT against GBM, including on-target/off-tumor toxicity, antigen modulation, tumor heterogeneity, and the immunosuppressive tumor microenvironment. We then present recent preclinical and clinical studies targeting well-characterized GBM antigens, which include the interleukin-13 receptor 2 and the epidermal growth factor receptor. Afterward, we turn our attention to alternative targets in GBM, including less-explored antigens such as B7-H3 (CD276), carbonic anhydrase IX, and the GD2 ganglioside. We also discuss additional target ligands, namely CD70, and natural killer group 2 member D ligands. Finally, we present the possibilities afforded by novel CAR architectures. In particular, we examine the use of armored CARs to improve the survival and proliferation of CAR T cells. We conclude by discussing the advantages of tandem and synNotch CARs when targeting multiple GBM antigens.
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