Prospective approaches to enhancing CAR T cell therapy for glioblastoma

Abstract

Glioblastoma (GBM) is the most common malignant brain tumor. The poor clinical outcome and overall ineffectiveness of current standard treatments, including surgery, chemotherapy, and radiation, highlight the urgent need for alternative tumor-specific therapies for GBM. Chimeric antigen receptor (CAR) T cell therapy is a revolutionary therapeutic strategy for hematological malignancies, but the optimal potency of CAR T cell therapy for solid tumors, especially GBM, has not been achieved. Although CAR T cell therapeutic strategies for GBM have been assessed in clinical trials, the current antitumor activity of CAR T cells remains insufficient. In this review, we present our perspective on genetically modifying CAR constructs, overcoming T cell dysfunctions, and developing additional treatments that can improve CAR T cell effectiveness, such as functionality, persistence, and infiltration into tumor sites. Effectively improved CAR T cells may offer patients with GBM new treatment opportunities, and this review is intended to provide a comprehensive overview for researchers to develop potent CAR T cells using genetic engineering or combinatorial preparations.

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

“…iCARs contain an inhibitory domain derived from immune checkpoint proteins which inhibit the binding to an antigen on non-malignant cells, but not on tumor cells. [ 16 , 25 , 38 ]. Another possibility to induce spatial control is to add the hypoxia-inducible factor 1 alpha degradation pathway in order to restrict CAR expression only to those CAR-T cells that infiltrate the hypoxic TME [ 25 , 94 ].…”

“…This leads to an activation of downstream killing pathways in the corresponding T cell [ 36 ]. Intraventricular injection with CAR-T-EGFRvIII.BiTE-EGFR cells not only induced complete and durable responses associated with prolonged survival in an orthotopic mouse model that received tumor cells of the human glioma U87 and U251 cell lines, as well as in PDXs, but also redirected non-specific bystander T cells and Tregs to become cytotoxic killers without on-target/off-tumor activity [ 37 , 38 ].…”

Sonodynamic therapy and Magnetic Resonance-guided Focused Ultrasound: new therapeutic strategy in Glioblastoma

“…Various new treatments have been proposed over the years, regarding use of CAR T cells [13], molecular agents enhancing the effect of Radiotherapy (RT) [14], up to the application of high and low intensity focus ultrasound [15].…”