T Cells Redirected to EphA2 for the Immunotherapy of Glioblastoma

Abstract

Outcomes for patients with glioblastoma (GBM) remain poor despite aggressive multimodal therapy. Immunotherapy with genetically modified T cells expressing chimeric antigen receptors (CARs) targeting interleukin (IL)-13Rα2, epidermal growth factor receptor variant III (EGFRvIII), or human epidermal growth factor receptor 2 (HER2) has shown promise for the treatment of gliomas in preclinical models and in a clinical study (IL-13Rα2). However, targeting IL-13Rα2 and EGFRvIII is associated with the development of antigen loss variants, and there are safety concerns with targeting HER2. Erythropoietin-producing hepatocellular carcinoma A2 (EphA2) has emerged as an attractive target for the immunotherapy of GBM as it is overexpressed in glioma and promotes its malignant phenotype. To generate EphA2-specific T cells, we constructed an EphA2-specific CAR with a CD28-ζ endodomain. EphA2-specific T cells recognized EphA2-positive glioma cells as judged by interferon-γ (IFN-γ) and IL-2 production and tumor cell killing. In addition, EphA2-specific T cells had potent activity against human glioma-initiating cells preventing neurosphere formation and destroying intact neurospheres in coculture assays. Adoptive transfer of EphA2-specific T cells resulted in the regression of glioma xenografts in severe combined immunodeficiency (SCID) mice and a significant survival advantage in comparison to untreated mice and mice treated with nontransduced T cells. Thus, EphA2-specific T-cell immunotherapy may be a promising approach for the treatment of EphA2-positive GBM.

Tandem CAR T cells targeting HER2 and IL13Rα2 mitigate tumor antigen escape

“…We and others have shown that experimental orthotopic GBM regresses after administration of HER2 or IL13Rα2 CAR T cells, yet tumors recur in 40%-60% of CAR T cell-treated animals (2)(3)(4)30). Therefore, we assessed the surface expression of HER2 and IL13Rα2 in a cohort of 3 primary GBM samples (unique patient numbers 1-3 [UPN 1-UPN 3]) obtained from surgical excision material (hereafter referred to as primary GBM).…”

“…Adoptive transfer of chimeric antigen receptor-grafted (CARgrafted) (1) T cells has induced tumor regression in several preclinical models of glioblastoma (GBM) (2)(3)(4), osteosarcoma (5,6), and neuroblastoma (7). However, only sporadic clinical responses have been observed in early-phase clinical trials for these tumors (8)(9)(10)(11).…”

CAR T Cells Targeting Podoplanin Reduce Orthotopic Glioblastomas in Mouse Brains

“…16), and ephrin type A receptor 2 (EphA2; ref. 17). In addition, CAR-transduced T cells can migrate through the microvascular walls and penetrate tumors (14,16).…”

Glioblastoma antigen discovery—foundations for immunotherapy

“…In a recent study by Chow et al T cells expressing CAR specific for EphA2 were able to attack and kill GBM cell lines in vitro and cause GBM tumor regression in mice [46]. EphA2 is a fairly novel antigen target and further studies are needed to elaborate on its significance in the treatment of GBM patients.…”