CD19-specific CAR-T cells encoding either CD28 or 4-1BB costimulatory endodomains promote antitumor activity in patients with B cell malignancies. Enhancing the kinetics of antitumor activity of 4-1BB, while preserving their longevity, may be critical in controlling rapidly progressive solid tumors. CD28 costimulation is generally associated with a very rapid tumor clearance as compared with 4-1BB, but also more pronounced propensity to exhaustion or less formation of memory T cells as indicated by their short-term persistence. The equilibrium of LCK/THEMIS-SHP1 can be genetically manipulated to modulate efficacy and safety of these CAR-T cells. LCK overexpression promotes T cell persistence without exhaustion since the antitumor response is maintained after tumor re-challenge. SHP1 can be pharmacologically recruited to the CAR synapse and can temporarily attenuate T cell function without eliminating CAR-T cells.
- THEMIS-SHP1 Recruitment by 4-1BB Tunes LCK-Mediated Priming of Chimeric Antigen Receptor-Redirected T Cells Cancer Cell. 2020 Jan 22. pii: S1535-6108(19)30584-7. doi: 10.1016/j.ccell.2019.12.014.