Knockout of LCK enables allogeneic CAR-T activity 4536

Abstract Description CAR-T technology has achieved significant success in treatment of certain liquid cancers, but many challenges hinder the development of this therapy, including the often poor quality and quantity of the patient’s own T cells, and the time taken to produce sufficient CAR-T cells for therapy. “Off-the-shelf” allo-CAR-T could solve these problems, but can potentially cause Graft versus Host Disease (GVHD). Additionally, autologous CAR-T cells have not so far been very effective against solid tumors. We recently showed that CD28-CAR signaling was triggered in the absence of the SRC family kinase LCK, which is essential for TCR signaling. We found that LCK-disrupted CAR-T cells (disLCK-CAR-T) signal strongly through CAR and have significantly better in vivo efficacy in both liquid and solid tumor models. This is because of their enhanced persistence, induction of memory, and reduced exhaustion phenotype. The disLCK-CAR-T blocks activation through endogenous TCR as well as TCR KO (TRAC-targeted) CAR-T, both methods blocking the development of GVHD. disLCK-CAR-T also shows superior in vivo persistence compared to TCR KO T cells, probably because of retained tonic signaling. This non-canonical signaling in CAR-T cells provides new insight into the initiation of TCR and CAR signaling and has important clinical implications for improvement of both autologous and allogeneic CAR-T cells. disLCK-CAR-T is being further developed as an allogeneic CAR-T. Funding Sources NMRC: MOH-000523; A*STAR Singapore Therapeutics Development Review (STDR) H23H9a0014 and H24H9a0005 Topic Categories Vaccines and Immunotherapy (VAC)