Pant Ayush, Lim Michael
Department of Neurosurgery, School of Medicine, Johns Hopkins University, Baltimore, MD 21218, USA.
Department of Neurosurgery, School of Medicine, Stanford University, Stanford, CA 94305, USA.
Cancers (Basel). 2023 Feb 16;15(4):1249. doi: 10.3390/cancers15041249.
Completed clinical trials of CAR-T cells in glioblastoma (GBM) have revealed key challenges that limit their efficacy. These include incomplete antigen coverage, downregulation of target antigen in response to therapy, exposure to immunosuppressive cells and cytokines in the tumor microenvironment and exhaustion of CAR-T cells. To overcome these challenges, CAR-T cells have been modified to maximize effector function and resist immunosuppression in the tumor while limiting toxicities to the host. Adoption of these novel CAR-T strategies in GBM can overcome the "cold tumor" phenotype of GBM and trigger an inflammatory cascade that maximizes tumor clearance and minimizes CAR-T dysfunction. To achieve this, understanding and harnessing the antigenic, metabolic and immunological composition of GBM is crucial. Here we review the findings from completed clinical trials of CAR-T cells in GBM as well as novel strategies that could improve CAR-T survival and function in the tumor.
嵌合抗原受体T细胞（CAR-T细胞）治疗胶质母细胞瘤（GBM）的临床试验已揭示了限制其疗效的关键挑战。这些挑战包括抗原覆盖不完全、治疗后靶抗原下调、肿瘤微环境中暴露于免疫抑制细胞和细胞因子以及CAR-T细胞耗竭。为了克服这些挑战，人们对CAR-T细胞进行了改造，以最大限度地发挥效应功能，在肿瘤中抵抗免疫抑制，同时限制对宿主的毒性。在GBM中采用这些新型CAR-T策略可以克服GBM的“冷肿瘤”表型，并引发炎症级联反应，从而最大限度地清除肿瘤并最小化CAR-T功能障碍。要实现这一点，了解和利用GBM的抗原、代谢和免疫组成至关重要。在此，我们回顾了CAR-T细胞治疗GBM的已完成临床试验的结果，以及可提高CAR-T细胞在肿瘤中的存活率和功能的新策略。
