Genetically Engineered T-Cells for Malignant Glioma: Overcoming the Barriers to Effective Immunotherapy

Abstract

Malignant gliomas carry a dismal prognosis. Conventional treatment using chemo- and radiotherapy has limited efficacy with adverse events. Therapy with genetically engineered T-cells, such as chimeric antigen receptor (CAR) T-cells, may represent a promising approach to improve patient outcomes owing to their potential ability to attack highly infiltrative tumors in a tumor-specific manner and possible persistence of the adaptive immune response. However, the unique anatomical features of the brain and susceptibility of this organ to irreversible tissue damage have made immunotherapy especially challenging in the setting of glioma. With safety concerns in mind, multiple teams have initiated clinical trials using CAR T-cells in glioma patients. The valuable lessons learnt from those trials highlight critical areas for further improvement: tackling the issues of the antigen presentation and T-cell homing in the brain, immunosuppression in the glioma microenvironment, antigen heterogeneity and off-tumor toxicity, and the adaptation of existing clinical therapies to reflect the intricacies of immune response in the brain. This review summarizes the up-to-date clinical outcomes of CAR T-cell clinical trials in glioma patients and examines the most pressing hurdles limiting the efficacy of these therapies. Furthermore, this review uses these hurdles as a framework upon which to evaluate cutting-edge pre-clinical strategies aiming to overcome those barriers.

CAR T cells for brain tumors: Lessons learned and road ahead

“…Much of what is known about immune cell infiltration into the brain is derived from models of infection or experimental autoimmune encephalomyelitis (EAE) . These barriers regulate extravasation through postcapillary vesicles and limit immune entry in the brain or CSF due to the presence of endothelial cell layers with tight junctions and astrocyte foot process known as glia limitans . From circulation, T cells must first adhere to vascular endothelium via a multitude of integrins, adhesion molecules, and chemokines .…”

“…ICV delivery bypasses all but the glia limitans in delivery to the brain parenchyma. Treating patients with locoregional delivery of CAR T cells has been reported in GBM as well as other malignant diseases including ovarian, lung, and breast cancers . For brain tumors, locoregional delivery requires implantation of a reservoir/catheter delivery device that is typically placed during surgical resection or biopsy, with the reservoir accessible under the scalp and the catheter placed to drain into the tumor bed/cavity or CSF.…”

“…197 These barriers regulate extravasation through postcapillary vesicles and limit immune entry in the brain or CSF due to the presence of endothelial cell layers with tight junctions and astrocyte foot process known as glia limitans. 198,199 From circulation, T cells must first adhere to vascular endothelium via a multitude of integrins, adhesion molecules, and chemokines. 198,199 Activated T cells, but not naive or resting memory T cells, 200 can be recruited beyond the BBB in the absence of inflammation although CD8 T cells require the presentation of MHC class I antigens on luminal endothelium.…”

“…198,199 From circulation, T cells must first adhere to vascular endothelium via a multitude of integrins, adhesion molecules, and chemokines. 198,199 Activated T cells, but not naive or resting memory T cells, 200 can be recruited beyond the BBB in the absence of inflammation although CD8 T cells require the presentation of MHC class I antigens on luminal endothelium. 201 Understanding how to best ensure optimal trafficking of CAR T cells to brain tumors remains an active area of investigation, and we will summarize some of the considerations below.…”

circKIF4A promotes tumorogenesis of glioma by targeting miR-139-3p to activate Wnt5a signaling

“…WHO class IV glioma, also known as glioblastoma or glioblastoma multiforme (GBM). GBM was found to be the most common malignant primary brain tumor, accounting for 16% of all primary brain tumors and 54% of all gliomas (Chuntova et al 2018), with high morbidity, high recurrence rate, high mortality and low cure rate (Chen et al 2018). Although surgical techniques and adjuvant therapy have evolved over the decades, the treatment and prognosis of gliomas still face significant challenges (Tomiyama and Ichimura 2019).…”