CAR T Cell Therapy in Primary Brain Tumors: Current Investigations and the Future.

Authors: Lin YJ, Mashouf LA, Lim M

Chimeric antigen receptor T cells (CAR T cells) are engineered cells expressing a chimeric antigen receptor (CAR) against a specific tumor antigen (TA) that allows for the identification and elimination of cancer cells. The remarkable clinical effect seen with CAR T cell therapies against hematological malignancies have attracted interest in developing such therapies for solid tumors, including brain tumors. Glioblastoma (GBM) is the most common primary brain tumor in adults and is associated with poor prognosis due to its highly aggressive nature. Pediatric brain cancers are similarly aggressive and thus are a major cause of pediatric cancer-related death. CAR T cell therapy represents a promising avenue for therapy against these malignancies. Several specific TAs, such as EGFR/EGFRvIII, IL13Rα2, B7-H3, and HER2, have been targeted in preclinical studies and clinical trials. Unfortunately, CAR T cells against brain tumors have showed limited efficacy due to TA heterogeneity, difficulty trafficking from blood to tumor sites, and the immunosuppressive tumor microenvironment. Here, we review current CAR T cell approaches in treating cancers, with particular focus on brain cancers. We also describe a novel technique of focused ultrasound controlling the activation of engineered CAR T cells to achieve the safer cell therapies. Finally, we summarize the development of combinational strategies to improve the efficacy and overcome historical limitations of CAR T cell therapy.

Introduction

Purpose Other

Study Objective To review current CAR T cell approaches for cancer—particularly brain tumors—describe a novel focused ultrasound method to control engineered CAR T cell activation, and summarize combinational strategies to improve their efficacy and safety.

Disease model Glioblastoma (GBM)

Cargo name and characteristics CAR T cells — engineered T cell therapy (cellular cargo): T lymphocytes expressing chimeric antigen receptors targeting tumor antigens (EGFR/EGFRvIII, IL13Rα2, B7-H3, HER2); discussion includes engineered/ultrasound-controllable CAR T designs for brain tumors

Outcomes and Safety

Summary of Outcomes CAR T cell therapy shows promise for brain and other solid tumors but has limited efficacy as a monotherapy due to tumor antigen heterogeneity, poor trafficking to tumor sites, and an immunosuppressive tumor microenvironment; combinatorial approaches (with radiotherapy, chemotherapy, and other immunotherapies) are suggested to improve outcomes. The paper describes a novel focused-ultrasound method to control activation of engineered CAR T cells, but it does not report specific ultrasound parameters as successful.

Safety-related matter The authors emphasize antigen selection to preserve normal tissues and minimize on-target/off-tumor toxicity and propose focused ultrasound control of CAR T activation to achieve safer therapies. No specific adverse effects or clinical safety events are reported in the provided excerpt.

Brain Region

Visualization unavailable

Ultrasound Parameters

Focal Characteristics Focal depth: None; Focal length: None; Aperture size: None

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