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

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.

The Interplay between Glioblastoma and Its Microenvironment

“…The use of T cells as immunotherapeutic tools has been explored in various malignancies including GBM. Chimeric antigen receptor (CAR) T cell therapy has been heavily investigated in several types of cancers [ 84 , 85 , 86 , 87 ]. These engineered T cells utilize tumor-associated antigens (TAAs) to allow T cells to become activated and gain greater specificity against tumor cells.…”

CAR T cells: Building on the CD19 paradigm

“…The first attempts to tackle solid tumors replicated the approaches established in B-cell malignancies, utilizing the same CAR designs (either 28z or BBz) and targeting a single antigen. While good responses have been sporadically obtained in Glioblastoma multiforme (GBM), head, and neck squamous cell carcinoma, and prostate cancer [55], the overall responses are not comparable to CD19 CAR therapy. One limitation owes to the paucity of potential targets that, like CD19, are expressed on the surface of nearly all tumor cells and only in dispensable normal cells.…”

Optimizing T Cell-Based Therapy for Glioblastoma

“…The 3 rd generation of CAR T cells, composed of multiple signaling domains such as CD28 and 4-1BB or Ox40. The most current generation CAR T cells, T cells redirected for universal cytokine-mediated killing (TRUCKS), have co-stimulatory molecules and are armed with transgenes to express a synthetic protein of interest such as immune stimulatory cytokines of IL-2, IL-5, IL-12 to exhibit an improved anti-tumor function and resistance to immunosuppressive tumor microenvironment ( 22 , 23 ).…”

“…Second and third generation CAR T cells added 4-1BB and CD28, which are co-stimulatory factors that improved activation and expansion ( 22 ). Fourth generation CAR T cells provide the ability to secrete a protein of interest such as cytokines and chemokines with enhanced T cell persistence and anti-tumor function ( 23 ).…”

“…domains such as CD28 and 4-1BB or Ox40. The most current generation CAR T cells, T cells redirected for universal cytokinemediated killing (TRUCKS), have co-stimulatory molecules and are armed with transgenes to express a synthetic protein of interest such as immune stimulatory cytokines of IL-2, IL-5, IL-12 to exhibit an improved anti-tumor function and resistance to immunosuppressive tumor microenvironment (22,23). Two FDA approved CAR T cell therapies are available for treatment of acute lymphoblastic leukemia (ALL) and diffuse large B cell lymphoma (DLBCL), Tisagenlecleucel (CTL019, Kymriah © ) and axicabtagene ciloleucel (Yescarta © ).…”