274 LCK knockout CAR-T cells as a novel allogeneic platform

Abstract

Background Chimeric antigen receptor (CAR) T therapy has shown remarkable success in treating liquid tumours but current approved therapies rely on autologous T cells which are expensive, difficult to manufacture and not readily available for patients whose disease progress rapidly. The production of safe and effective allogeneic CAR-T cells is needed to increase accessibility of CAR-T therapy and broaden its application. The main approach to generate allogeneic CAR-T therapy is by disrupting T cell receptor (TCR) expression to minimize Graft-versus-Host Disease (GVHD) mediated through the TCR of donor cells against the recipient's major histocompatibility complex (MHC). However, the TCR disruption approach has shown limited persistence in vivo [1] and in clinical trials [2] unlike the long term durability of autologous CAR-T cells.Here, we propose a novel platform for allogeneic CAR-T therapy that retains the TCR but inhibits TCR signalling by knocking out the Lymphocyte-specific protein tyrosine kinase (LCK)a well-established kinase for proximal TCR activation. This builds on the discovery that our second generation CD28-CAR can be activated independently of LCK unlike the endogenous TCR.