T cells redirected to EphA2 for the immunotherapy of glioblastoma.
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.
The Methodist Hospital, Baylor College of Medicine, Houston, TX, USA.
Kevin K H
KK
Chow
Swati
S
Naik
Sunitha
S
Kakarla
Vita S
VS
Brawley
Donald R
DR
Shaffer
Zhongzhen
Z
Yi
Nino
N
Rainusso
Meng-Fen
MF
Wu
Hao
H
Liu
Yvonne
Y
Kew
Robert G
RG
Grossman
Suzanne
S
Powell
Dean
D
Lee
Nabil
N
Ahmed
Stephen
S
Gottschalk
D019264:Adoptive Transfer; D000818:Animals; D045744:Cell Line, Tumor; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D005909:Glioblastoma / Q000628:therapy*; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D020014:K562 Cells; D008297:Male; D051379:Mice; D016513:Mice, SCID; D036104:Receptor, EphA2 / Q000235:genetics*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology*; D014161:Transduction, Genetic
D007371:Interferon-gamma; D007376:Interleukin-2; D036104:Receptor, EphA2; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human