Orthogonal cytokine engineering enables novel synthetic effector states escaping canonical exhaustion in tumor-rejecting CD8+ T cells

Coukos, Corria-Osorio and colleagues use an orthogonal genetic approach to engineer CD8(+) T cells into better effector synthetic cells for antitumor adoptive cell therapy. This approach generates engineered effector T cells that express an IL-2 variant, IL-33 and a programmed cell death protein 1 decoy. To date, no immunotherapy approaches have managed to fully overcome T-cell exhaustion, which remains a mandatory fate for chronically activated effector cells and a major therapeutic challenge. Understanding how to reprogram CD8(+) tumor-infiltrating lymphocytes away from exhausted effector states remains an elusive goal. Our work provides evidence that orthogonal gene engineering of T cells to secrete an interleukin (IL)-2 variant binding the IL-2R beta gamma receptor and the alarmin IL-33 reprogrammed adoptively transferred T cells to acquire a novel, synthetic effector state, which deviated from canonical exhaustion and displayed superior effector functions. These cells successfully overcame homeostatic barriers in the host and led-in the absence of lymphodepletion or exogenous cytokine support-to high levels of engraftment and tumor regression. Our work unlocks a new opportunity of rationally engineering synthetic CD8(+) T-cell states endowed with the ability to avoid exhaustion and control advanced solid tumors.