胶质母细胞瘤嵌合抗原受体的研究现状与展望

IF 4.1 Q2 IMMUNOLOGY Immunotherapy advances Pub Date : 2022-06-01 DOI:10.1093/immadv/ltac014
Josephine Zhang, Jesús A. Siller-Farfán
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引用次数: 2

摘要

摘要多形性胶质母细胞瘤(GBM)是中枢神经系统中最恶性的癌症;表达嵌合抗原受体(CARs)的T细胞的过继细胞转移(ACT)已显示出对血液系统恶性肿瘤,即白血病和多发性骨髓瘤的显著成功。然而,CAR T细胞治疗实体瘤,尤其是GBM,仍然面临着阻碍其广泛应用的挑战。在这里,我们首先建立了ACT对抗GBM的障碍,包括靶向/肿瘤外毒性、抗原调节、肿瘤异质性和免疫抑制肿瘤微环境。然后,我们介绍了最近针对特征良好的GBM抗原的临床前和临床研究,这些抗原包括白细胞介素13受体α2和表皮生长因子受体。之后,我们将注意力转向GBM中的替代靶点,包括较少探索的抗原,如B7-H3(CD276)、碳酸酐酶IX和GD2神经节苷脂。我们还讨论了额外的靶配体,即CD70和自然杀伤第2组成员D配体。最后,我们展示了新型CAR架构所提供的可能性。特别是,我们研究了使用铠装CAR来提高CAR T细胞的存活和增殖。最后,我们讨论了串联和synNotch CARs在靶向多种GBM抗原时的优势。
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Current and future perspectives of chimeric antigen receptors against glioblastoma
Abstract 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 α2 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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审稿时长
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