Targeting death receptor pathways to enhance met-car t cell therapy in glioblastoma

The National Institute of Neurological Disorders and Stroke awarded East Tennessee State University $608,000 on September 1, 2026, under the Extramural Research Programs in the Neurosciences and Neurological Disorders program (CFDA 93.853) to develop and characterize MET-directed chimeric antigen receptor (MET-CAR) T cell therapy for glioblastoma, with focus on targeting death receptor pathways to enhance therapeutic efficacy.

The research addresses MET receptor overexpression in glioblastoma patients, which drives glioma stem cell survival, invasive repopulation, and resistance to bevacizumab, radiation, and chemotherapy. The project targets dual mechanisms: MET-positive tumor cells via CAR T cells engineered to recognize MET, and bystander killing of MET-negative glioblastoma cells through death receptor 5 (DR5) activation induced by ionizing radiation. Aim 1 characterizes ionizing radiation-induced death receptor pathway activation in glioblastoma and molecular mechanisms governing MET-CAR T cell responsiveness in vitro. Aim 2 implements ionizing radiation combined with MET-CAR T cells to improve therapeutic potency, leveraging TRAIL-mediated apoptosis triggered by CAR T cell death ligand production as a bystander effect.

The award period runs through August 31, 2030, with work performed in Johnson City, Tennessee. This is a Project Grant assistance type supporting basic and translational cancer immunotherapy research aligned with NINDS's mission to reduce the burden of neurological disease.

Abstract

Overexpression of met receptor tyrosine kinase (RTK) frequently occurs in GBM patients and is highly associated with bevacizumab resistance. Aberrant met activation promotes glioma stem cell (GSC) survival, invasive repopulation, and therapeutic resistance to radiation and chemotherapy. To target met-driven gscs, we have developed novel met-directed chimeric antigen receptor (met-car) t cells selectively targeting met- positive tumors in preclinical models. Although car t cell therapy has made promising progress in cancer immunotherapy, the therapeutic efficacy has been limited in solid tumors. While tumor cells can produce inhibitory cytokines suppressing car t cell activity, the nature of GBM heterogeneity further limits car t cell effectiveness. The overall goal of this application is to enhance met-car t cell potency through dual-targeting radiation-activated death receptor 5 (DR5) in GBM. Ionizing radiation (IR) is a standard-of-care therapy for targeting GBM. Recent studies showed that noncurative IR at optimal dose can upregulate death receptor (DR) expression in treated tumor cells, inducing apoptosis and cell death of both antigen-positive and -negative tumor cells via DR ligands released by activated car t cells. Particularly, DR5-mediated apoptosis through TNF- related apoptosis-inducing ligand (trail) is of high clinical significance for its selectively inducing apoptosis in tumor but not normal cells. We hypothesize that applying IR as a molecular switch to upregulate DR5 expression in GBM will enable met-car t cells to kill both met-positive and -negative GBM cells via trail production as a bystander effect, leading to improved therapeutic potency. In aim 1, we will characterize IR-induced DR pathway activation in GBM and the molecular mechanisms regulating met-car t cell responsiveness in vitro. Aim 2 will implement IR with met-car t cells to improve the therapeutic efficacy using GBM-PDX models in vivo. In aim 3, we will engineer met-car t cells to express trail to further improve met-car t cell potency. If successful, this approach will enhance the clinical paradigms by providing a novel combination strategy for treating malignant GBM. For student involvement, this project will teach modern cancer biology and immunotherapy concepts with hands-on experience, providing excellent student training opportunities for medical students, biomedical science graduate and undergraduate students in the field of cancer research.