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Next Generation CAR T Cells for the Immunotherapy of High-Grade Glioma

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Next Generation CAR T Cells for the Immunotherapy of High-Grade Glioma

Christopher T Petersen et al. Front Oncol.

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.

Keywords: CAR T cells; adoptive cell transfer (ACT); cell engineering; gene editing crispr; glioblastoma.

Figures

Figure 1
Figure 1
Next generation CAR T cells have potential to overcome factors influencing limited CAR T cell effector function in gliomas. A variety of both T cell and tumor-intrinsic factors add to the lack of efficacy in brain tumors. Limited T cell persistence, exhaustion, poor trafficking, and a hostile tumor microenvironment, defined by immunosuppressive cell populations and molecules, as well as antigen escape contribute to CAR T cell dysfunction and disappointing clinical results. Each of these challenges is being addressed by the development of the next generation of CAR T cell therapies through transgenic gene expression, inducible systems, gene editing, and multi-antigen targeting. Major immunosuppressive cell populations and molecules along with the genetic strategies currently being tested to overcome them are depicted in the figure. *Challenges/issues reported from clinical trial results.

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