Chimeric antigen receptor (CAR)-T cell therapy is now approved in the United States and Europe as a standard treatment for relapsed/refractory B-cell malignancies. It has also been approved recently by the Therapeutic Goods Administration in Australia and may soon be publicly reimbursed. This advance has accentuated scientific, clinical and commercial interest in adapting this exciting technology for the treatment of solid cancers where it is widely recognised that the challenges of overcoming a hostile tumor microenvironment are most acute. Indeed, CAR-T cell technology may be of the greatest value for those cancers that lack pre-existing immunity because they are immunologically 'cold', or have a low somatic tumor mutation load, or both. These cancers are generally not amenable to therapeutic immune checkpoint blockade, but CAR-T cell therapy may be effective because it provides an abundant supply of autologous tumor-specific T cells. This is achieved by using genetic engineering to re-direct autologous T-cell cytotoxicity towards a tumor-associated antigen, bypassing endogenous T-cell requirements for antigen processing, MHC-dependent antigen presentation and co-stimulation. One of the most challenging solid cancers is glioblastoma, which has among the least permissive immunological milieu of any cancer, and which is almost always fatal. Here, we argue that CAR-T cell technology may counter some glioblastoma defences and provide a beachhead for furthering our eventual therapeutic aims of restoring effective antitumor immunity. Although clinical investigation of CAR-T cell therapy for glioblastoma is at an early stage, we discuss three recently published studies, which feature significant differences in target antigen, CAR-T cell phenotype, route of administration and tumor response. We discuss the lessons, which may be learned from these studies and which may guide further progress in the field.

中文翻译：

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临床嵌合抗原受体-T 细胞疗法：一种新的、有前景的胶质母细胞瘤治疗方式。

嵌合抗原受体 (CAR)-T 细胞疗法现已在美国和欧洲被批准作为复发/难治性 B 细胞恶性肿瘤的标准治疗方法。它最近也获得了澳大利亚治疗用品管理局的批准，可能很快就会公开报销。这一进展突出了将这一激动人心的技术应用于实体癌治疗的科学、临床和商业兴趣，人们普遍认为，克服敌对肿瘤微环境的挑战最为严峻。事实上，CAR-T 细胞技术可能对那些缺乏预先存在的免疫力的癌症具有最大的价值，因为它们在免疫学上是“冷的”，或者体细胞肿瘤突变负荷低，或者两者兼而有之。这些癌症通常不适合治疗性免疫检查点阻断，但 CAR-T 细胞疗法可能是有效的，因为它提供了大量的自体肿瘤特异性 T 细胞。这是通过使用基因工程将自体 T 细胞的细胞毒性重新导向肿瘤相关抗原，绕过抗原加工、MHC 依赖性抗原呈递和共刺激的内源性 T 细胞要求来实现的。最具挑战性的实体癌症之一是胶质母细胞瘤，它是所有癌症中免疫环境最不宽容的一种，并且几乎总是致命的。在这里，我们认为 CAR-T 细胞技术可能会对抗一些胶质母细胞瘤的防御，并为进一步实现我们恢复有效抗肿瘤免疫的最终治疗目标提供一个滩头阵地。尽管针对胶质母细胞瘤的 CAR-T 细胞疗法的临床研究还处于早期阶段，但我们讨论了最近发表的三项研究：它们在靶抗原、CAR-T 细胞表型、给药途径和肿瘤反应方面存在显着差异。我们讨论了可以从这些研究中吸取的教训，并可以指导该领域的进一步进展。