ABSTRACT

Glioblastoma multiforme (GBM) is the deadliest human brain tumor with a median survival following diagnosis of 14–16 months. Innovative therapeutic approaches are urgently needed. Cancer stem cells (CSC) from GBM resist current chemo- and radiotherapies and can generate recurrent and aggressive tumors. To envisage innovative therapeutic approaches of potential clinical use, we engineered T cells with Fcγ-chimeric receptors (CRs) to elicit antibody-dependent cellular cytotoxicity (ADCC) in the presence of mAbs specific for tumor associated antigens (TAA). Indeed, in previous studies, we successfully redirected CD16158V-CR T cells against KRAS-mutated colorectal carcinoma cells. Since surface overexpression of epidermal growth factor receptor (EGFR) is frequently detectable in GBM, we assessed, in vitro, the anti-GBM potential of polymorphic CD16-CR T cells, in combination with anti-EGFR mAbs, on GBM-derived EGFR+ CSC.
Our results indicate that CD16158V, but not CD16158FCR engineered T cells incubated with cetuximab, but not panitumumab, induced the elimination of GBM-derived CSC through a caspase-3 dependent mechanism, and produced high amounts of TNFα and IFNγ upon recognition of target cells. These data pave the way towards pre-clinical development of innovative GBM treatments, taking advantage of CD16158V-CR engineered T cells and therapeutic antibodies.

IMPACT STATEMENT

We present an innovative therapeutic strategy in which anti-EGFR monoclonal antibody, cetuximab redirects CD16158V-chimeric receptor T cells against MB stem cells, these findings may support a potential role of CD16-CR T cell-based immunotherapy in the management of EGFR+ GBM.