Chimeric antigen receptor T-cell therapy in glioblastoma: charging the T cells to fight

Craig A Land,Phillip R Musich,Dalia Haydar,Qian Xie,Giedre Krenciute

doi:10.1186/s12967-020-02598-0

Abstract

Glioblastoma multiforme (GBM) is the most common malignant brain cancer that invades normal brain tissue and impedes surgical eradication, resulting in early local recurrence and high mortality. In addition, most therapeutic agents lack permeability across the blood brain barrier (BBB), further reducing the efficacy of chemotherapy. Thus, effective treatment against GBM requires tumor specific targets and efficient intracranial drug delivery. With the most recent advances in immunotherapy, genetically engineered T cells with chimeric antigen receptors (CARs) are becoming a promising approach for treating cancer. By transducing T lymphocytes with CAR constructs containing a tumor-associated antigen (TAA) recognition domain linked to the constant regions of a signaling T cell receptor, CAR T cells may recognize a predefined TAA with high specificity in a non-MHC restricted manner, and is independent of antigen processing. Active T cells can travel across the BBB, providing additional advantage for drug delivery and tumor targeting. Here we review the CAR design and technical innovations, the major targets that are in pre-clinical and clinical development with a focus on GBM, and multiple strategies developed to improve CAR T cell efficacy.

Highlights

Glioblastoma (GBM), WHO grade IV glioma, is the most devastating brain tumor in adults [1]
A strategy is to further engineer T cells to overexpress transgenic proteins such as cytokines and chemokines that are known to stimulate T cell proliferation and persistence. Such chimeric antigen receptor (CAR) T cells are known as “T cells redirected for universal cytokine-mediated killing”, socalled TRUCKs or the 4th generation CARs [23] (Fig. 1b)
GBM harboring MET amplification or hepatocyte growth factor (HGF) autocrine activation are sensitive to MET inhibitors in preclinical models [82, 83], recent clinical trials further showed that a combination of MET and VEGF inhibitors significantly improved progression free survival (PFS) and overall survival (OS) in the mesenchymal subtype of recurrent GBM patients with high tumor HGF expression [84]

Summary

Introduction

Glioblastoma (GBM), WHO grade IV glioma, is the most devastating brain tumor in adults [1]. Genetic modification to improve CAR T cell persistence and safety Since CAR T-cell therapy showed promising but limited anti-tumor response in GBM clinical trials in 1990s, efforts have been made to improve CAR T-cell efficacy.

Results

Conclusion