Enhancing cancer targeting of γ9δ2TCR through modified NKG2D co-stimulation

Abstract

Despite the ability of γδT 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 αβT cells engineered to express a defined γδTCR (TEG) has been developed. TEGs are αβT cells engineered to express a defined γδTCR. These cells are able to mediate effective antitumor reactivity without showing any reactivity towards healthy tissue, and combine the best qualities of both αβT and γδT cells. In fact, the high affinity γ9δ2TCR 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 γδTCR-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-CD28_wt and NKG2D-4-1BB_CD28TM improved the activity of TEG001 against tumors that were recognized by γδTCR-Cl5 and expressed NKG2D ligands, but did not affect tumors that either were not recognized by γδTCR-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.