Proposing a tandem AND-gate CAR T cell targeting glioblastoma multiforme

Abstract

CAR T cell therapy is suggested as an effective method to treat hematological malignancies. However, high recurrence rates and in vivo toxicities have limited their widespread use. In order to reduce toxicity and improve tumor specificity, we propose a CAR T cell targeting glioblastoma multiforme utilizing the synNotch receptor pathway linked to a tandem CAR T cell. The extracellular domain of the synNotch receptor is replaced by a single chain fragment variable specific for the EGF receptor variant III (scfv-EGFRvIII), and covalently bonded to a IL-13Rα2-CD133-tandem CAR. This would produce an AND-gate CAR-T cell, which requires activation of both signals from synNotch receptor binding to EGFRvIII and then binding of the tandem CAR to either of the two IL-13Rα2 or CD133 ligands-specific antigens for glioblastoma stem cells. SynNotch receptor activation along with the 4-1BB costimulatory domain results in CAR T cell expression under the TRE promoter, culminating in a tri-specific and effective tumor stem cell recognition and elimination of glioblastoma multiforme.