Chimeric Antigen Receptor T Cells in Glioblastoma-Current Concepts and Promising Future.

Glioblastoma (GBM) is a highly aggressive primary brain tumor that is largely refractory to treatment and, therefore, invariably relapses. GBM patients have a median overall survival of 15 months and, given this devastating prognosis, there is a high need for therapy improvement. One of the therapeutic approaches currently tested in GBM is chimeric antigen receptor (CAR)-T cell therapy. CAR-T cells are genetically altered T cells that are redirected to eliminate tumor cells in a highly specific manner. There are several challenges to CAR-T cell therapy in solid tumors such as GBM, including restricted trafficking and penetration of tumor tissue, a highly immunosuppressive tumor microenvironment (TME), as well as heterogeneous antigen expression and antigen loss. In addition, CAR-T cells have limitations concerning safety, toxicity, and the manufacturing process. To date, CAR-T cells directed against several target antigens in GBM including interleukin-13 receptor alpha 2 (IL-13Rα2), epidermal growth factor receptor variant III (EGFRvIII), human epidermal growth factor receptor 2 (HER2), and ephrin type-A receptor 2 (EphA2) have been tested in preclinical and clinical studies. These studies demonstrated that CAR-T cell therapy is a feasible option in GBM with at least transient responses and acceptable adverse effects. Further improvements in CAR-T cells regarding their efficacy, flexibility, and safety could render them a promising therapy option in GBM.

Layer-specific impairment in the developing lateral entorhinal cortex of immune-challenged Disc1+/- mice.

Cognitive deficits in mental disorders result from dysfunctional activity in large-scale brain networks centred around the hippocampus and the prefrontal cortex. Dysfunctional activity emerges early during development and precedes the cognitive disabilities. The prefrontal-hippocampal network is driven by a prominent input from the lateral entorhinal cortex. We have previously shown that during early development, the entorhinal drive of the prefrontal-hippocampal network is impaired in a mouse model of mental disorders, yet the cellular substrate of this impairment is still poorly understood. Here, we address this question by a detailed characterization of projection neurons across the layers of the lateral entorhinal cortex in immune-challenged Disc1+/- mice at the beginning of the second postnatal week. We found that the activity and morphology of neurons in layers 2b and 3, which project to the hippocampus, are impaired. Neurons in layer 2b show increased spike-frequency adaptation, whereas neurons in layer 3 have reduced dendritic complexity but increased spike density. These findings identify the developmental alterations of entorhinal-hippocampal communication that underlie network dysfunction in immune-challenged Disc1+/- mice. KEY POINTS: Neonatal immune-challenged Disc1+/- mice show layer-specific changes in the lateral entorhinal cortex. Entorhinal layer 2b pyramidal neurons have increased spike-frequency adaptation. Reduced dendritic complexity but increased spine density characterize layer 3 pyramidal neurons.

Developmental decrease of entorhinal-hippocampal communication in immune-challenged DISC1 knockdown mice.

The prefrontal-hippocampal dysfunction that underlies cognitive deficits in mental disorders emerges during early development. The lateral entorhinal cortex (LEC) is tightly interconnected with both prefrontal cortex (PFC) and hippocampus (HP), yet its contribution to the early dysfunction is fully unknown. Here we show that mice that mimic the dual genetic (G) -environmental (E) etiology (GE mice) of psychiatric risk have poor LEC-dependent recognition memory at pre-juvenile age and abnormal communication within LEC-HP-PFC networks throughout development. These functional and behavioral deficits relate to sparser projections from LEC to CA1 and decreased efficiency of axonal terminals to activate the hippocampal circuits in neonatal GE mice. In contrast, the direct entorhinal drive to PFC is not affected, yet the PFC is indirectly compromised, as target of the under-activated HP. Thus, the entorhinal-hippocampal circuit is already impaired from neonatal age on in GE mice.