Novel high‐affinity EGFRvIII‐specific chimeric antigen receptor T cells effectively eliminate human glioblastoma

• Published in: Clinical & translational immunology Vol. 10; no. 5; pp. e1283 - n/a
• Main Authors: Abbott, Rebecca C, Verdon, Daniel J, Gracey, Fiona M, Hughes‐Parry, Hannah E, Iliopoulos, Melinda, Watson, Katherine A, Mulazzani, Matthias, Luong, Kylie, D’Arcy, Colleen, Sullivan, Lucy C, Kiefel, Ben R, Cross, Ryan S, Jenkins, Misty R
• Format: Journal Article
• Language: English
• Published: Australia John Wiley & Sons, Inc 2021; John Wiley and Sons Inc; Wiley
• Subjects: Affinity; Antibodies; Antigens; Antitumor activity; Brain cancer; Brain tumors; CAR T cells; Cell therapy; Chimeric Antigen Receptor (CAR); Chimeric antigen receptors; Clinical trials; Cloning; Cytokines; EGFRvIII; Epidermal growth factor; Flow cytometry; Glioblastoma; Glioma; Immunotherapy; Lymphocytes; Lymphocytes T; Monoclonal antibodies; Mutation; Original; Patients; Peptides; Proteins; Radiation therapy; Solid tumors; T cells; Tumors; Vaccines; Xenografts; CAR T cells; glioblastoma; immunotherapy; EGFRvIII; Chimeric Antigen Receptor (CAR); brain cancer; T cells
• ISSN: 2050-0068; 2050-0068
• DOI: 10.1002/cti2.1283

Objectives The increasing success of Chimeric Antigen Receptor (CAR) T cell therapy in haematological malignancies is reinvigorating its application in many other cancer types and with renewed focus on its application to solid tumors. We present a novel CAR against glioblastoma, an aggressive, malignant glioma, with a dismal survival rate for which treatment options have remained unchanged for over a decade. Methods We use the human Retained Display (ReD) antibody platform (Myrio Therapeutics) to identify a novel single‐chain variable fragment (scFv) that recognises epidermal growth factor receptor mutant variant III (EGFRvIII), a common and tumor‐specific mutation found in glioblastoma. We use both in vitro functional assays and an in vivo orthotopic xenograft model of glioblastoma to examine the function of our novel CAR, called GCT02, targeted using murine CAR T cells. Results Our EGFRvIII‐specific scFv was found to be of much higher affinity than reported comparators reverse‐engineered from monoclonal antibodies. Despite the higher affinity, GCT02 CAR T cells kill equivalently but secrete lower amounts of cytokine. In addition, GCT02‐CAR T cells also mediate rapid and complete tumor elimination in vivo. Conclusion We present a novel EGFRvIII‐specific CAR, with effective antitumor functions both in in vitro and in a xenograft model of human glioblastoma. We have made novel chimeric antigen receptor T (CART) cells specific for glioblastoma, a devastating brain tumor with poor survival. This receptor is of extremely high affinity, and the CAR T cells can completely clear brain tumors in mice.