Enhancing cancer targeting of γ9δ2TCR through modified NKG2D co-stimulation

Abstract

Despite the ability of {gamma}{delta}T cells to mediate tumor killing independently of MHC recognition, all the clinical trials that have been carried out using these cells showed low response rate in patients, in part due to its poor proliferation ability. Recently, a new generation of CAR-T cells called {beta}T cells engineered to express a defined {gamma}{delta}TCR (TEG) has been developed. TEGs are {beta}T cells engineered to express a defined {gamma}{delta}TCR. These cells are able to mediate effective antitumor reactivity without showing any reactivity towards healthy tissue, and combine the best qualities of both {beta}T and {gamma}{delta}T cells. In fact, the high affinity {gamma}9{delta}2TCR clone 5 has recently been selected within the TEG format as a clinical candidate (TEG001). Here we present a strategy to improve the antitumor activity of TEG001 by co-expressing an activating chimeric co-receptor together with {gamma}{delta}TCR-Cl5.Therefore, we developed three different co-receptors by fusing the extracellular domain of the activating cell surface receptor NKG2D, that is able to bind stress induced ligands typically expressed on tumor cells, to the cytoplasmic signaling domains of the T cell costimulatory proteins ICOS, CD28 and 4-1BB. We determined that introduction of the chimeric co-receptors NKG2D-CD28wt and NKG2D-4-1BBCD28TM improved the activity of TEG001 against tumors that were recognized by {gamma}{delta}TCR-Cl5 and expressed NKG2D ligands, but did not affect tumors that either were not recognized by {gamma}{delta}TCR-Cl5 or did not express NKG2D ligands. This chimeric co-receptors approach open a wide range of opportunities that lead to a next generation of TEGs.