Abstract
High grade gliomas (HGG) comprise a heterogeneous group of brain malignancies with dismal prognosis. Current standard-of-care includes radiation, chemotherapy, and surgical resection when possible. Despite advances in each of these treatment modalities, survival rates for pediatric and adult HGG patients has remained largely unchanged over the course of several years. This is in stark contrast to the significant survival increases seen recently for a variety of hematological and other solid malignancies. The introduction and widespread use of immunotherapies have contributed significantly to these survival increases, and as such these therapies have been explored for use in the treatment of HGG. In particular, chimeric antigen receptor (CAR) T cell therapy has shown promise in clinical trials in HGG patients. However, unlike the tremendous success CAR T cell therapy has seen in B cell leukemia and lymphoma treatment, the success in HGG patients has been modest at best. This is largely due to the unique tumor microenvironment in the central nervous system, difficulty in accessing the tumor site, and heterogeneity in target antigen expression. The results of these features are poor CAR T cell proliferation, poor persistence, suboptimal cytokine secretion, and the emergence of antigen-loss tumor variants. These issues have called for the development of “next generation” CAR T cells designed to circumvent the barriers that have limited the success of current CAR T cell technologies in HGG treatment. Rapid advancements in gene editing technologies have provided several avenues for CAR T cell modification to enhance their efficacy. Among these are cytokine overexpression, gene knock-out and knock-in, targeting of multiple antigens simultaneously, and precise control of CAR expression and signaling. These “next generation” CAR T cells have shown promising results in pre-clinical models and may be the key to harnessing the full potential of CAR T cells in the treatment of HGG.
Highlights
The use of adoptively-transferred T cells as an anti-cancer therapeutic is a concept that has been explored extensively over the past several years
Despite the observed tumor relapse, this study showed that genetic modification of chimeric antigen receptor (CAR) T cells, in this particular case—cytokine overexpression, can be a powerful method to greatly improve CAR T cell function and persistence
The mechanism of antigen loss is currently under active investigation as downregulation of the target antigen and/or clonal expansion of antigen-negative tumor cells may contribute to this phenomenon. These findings indicate a need to target multiple antigens to enable CAR T cells to eliminate all brain tumor cells and avoid tumor recurrence
Summary
The use of adoptively-transferred T cells as an anti-cancer therapeutic is a concept that has been explored extensively over the past several years. While the majority of pre-clinical studies using these CAR T cells have been performed in models of B cell malignancies and solid tumors, the same strategies can be employed to improve CAR T cells for use in high grade gliomas. Generation gene-modified CAR T cells are an attractive approach to overcome both the T cell and tumor-intrinsic factors that have resulted in poor CAR T efficacy in high grade gliomas.
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