Future development of chimeric antigen receptor T cell therapies for patients suffering from malignant glioma

Abstract

Purpose of reviewChimeric antigen receptor (CAR) T cell therapy has been successful in some haematologic malignancies, but the central nervous system (CNS) presents unique obstacles to its use against tumours arising therein. This review discusses recent improvements in the delivery and design of these cells to improve the efficacy and safety of this treatment against malignant gliomas.Recent findingsThe immunosuppressive environment of the CNS affects the functionality of CAR T cells, but recent developments using metabolic manipulation and cytokine delivery have shown that the performance of CAR T cells can be improved in this environment. Emerging techniques can improve the delivery of CAR T cells to the CNS parenchyma, which is normally well protected from peripheral immune cells. The implementation of novel antigens and CAR-expression regulation strategies will improve the specificity and efficacy of these cells. Finally, although autologous T cells have historically been the standard, recent developments have made the use of allogeneic T cells or natural killer (NK) cells more clinically feasible.SummaryThe discoveries highlighted in this review will aid the development of CAR cells that are safer, more resilient against immunosuppressive signals in the CNS, and able to specifically target intracranial tumour cells.

Enhancing CAR-T cell metabolism to overcome hypoxic conditions in the brain tumor microenvironment

“…In this study, we grappled with the pivotal challenge of enhancing the efficacy of immunotherapy against GBM, an unrelenting brain tumor known for its resistance to conventional treatments. The intricate microenvironment of GBM, characterized by immunosuppression and hypoxic conditions, presents significant obstacles to successful immunotherapy outcomes ( 5 ). To surmount these challenges, we delved into the potential of metabolic conditioning to enhance the functional capabilities of CAR-T cells within this complex milieu.…”

“…One of the key challenges to successful immunotherapy in GBM is the highly immunosuppressive tumor microenvironment characterized by a number of mechanisms ( 2 ), including hypoxic conditions ( 3 ). As such, recent research has focused on developing innovative strategies to overcome these challenges and improve the effectiveness of immunotherapy ( 4 , 5 ).…”

“…Chimeric antigen receptor T cell (CAR-T) therapy has demonstrated significant efficacy against hematologic malignancies ( 6 ). However, its therapeutic potential remains limited against solid tumors, including brain neoplasms ( 5 ). The metabolic status of immune cells has recently been recognized as a critical factor in cancer immunotherapy.…”

Enhancing CAR-T Cell Metabolism to Overcome Hypoxic Conditions in the Brain Tumor Microenvironment

“…In this study, we grappled with the pivotal challenge of enhancing the efficacy of immunotherapy against GBM, an unrelenting brain tumor known for its resistance to conventional treatments. The intricate microenvironment of GBM, characterized by immune suppression and hypoxic condition, presents significant obstacles to successful immunotherapy outcomes (5). To surmount these challenges, we delved into the potential of metabolic conditioning to enhance the functional capabilities of CAR-T cells within this complex milieu.…”

“…One of the key challenges to successful immunotherapy in GBM is the highly immunosuppressive tumor microenvironment characterized by a number of mechanisms (2), including hypoxic conditions (3). As such, recent research has focused on developing innovative strategies to overcome these challenges and improve the effectiveness of immunotherapy (4,5).…”