autologous anti-EGFRvIII synNotch receptor-induced anti-EphA2/IL-13Ralpha2 CAR-T cells

A preparation of autologous T lymphocytes engineered to express a synthetic Notch (synNotch) receptor targeting epidermal growth factor receptor variant III (EGFRvIII) that induces the expression of a chimeric antigen receptor (CAR) specific for Ephrin receptor A2 (EphA2) and interleukin-13 receptor alpha 2 (IL13Ra2) upon antigen binding, with potential immunostimulating and antineoplastic activities. After isolation, transduction, expansion and reintroduction into the patient, autologous anti-EGFRvIII synNotch receptor-induced anti-EphA2/IL-13Ralpha2 CAR-T cells target and bind to EGFRvIII-expressing tumor cells, which induces the expression of CAR specific for EphA2 and IL13Ra2. This induces selective toxicity in EphA2-expressing and IL13Ra2-expressing tumor cells locally. EGFRvIII, an in-frame deletion of exons 2-7 in the EGFR gene, is overexpressed by a variety of cancer cell types but absent in normal, healthy cells. It plays a key role in tumor cell proliferation, tumor angiogenesis and resistance to both radio- and chemotherapy. IL13Ra2, a cancer-associated receptor, is overexpressed by a variety of tumor cell types; it is associated with increased invasiveness of tumor cells. EphA2, a member of the ephrin family of receptor tyrosine kinases (RTKs) involved in mammalian development, is overexpressed by a variety of different cancer cell types. EphA2 expression is associated with poor prognosis.