Clinical development of allogeneic chimeric antigen receptor αβ-T Cells.

Abstract

Ready-made banks of allogeneic chimeric antigen receptor (CAR) T cells, produced to be available at the time of need, offer the prospect of accessible and cost-effective cellular therapies. Various strategies have been developed to overcome allogeneic barriers, drawing on cell engineering platforms including RNA interference, protein-based restriction and genome editing, including RNA-guided CRISPR-Cas and base editing tools. Alloreactivity and the risk of graft versus host disease from non-matched donor cells have been mitigated by disruption of αβ-T cell receptor expression on the surface of T cells, and stringent removal of any residual αβ-T cell populations. In addition, host mediated rejection has been tackled through a combination of augmented lymphodepletion and cell engineering strategies that have allowed infused cells to evade immune recognition or conferred resistance to lymphodepleting agents to promote persistence and expansion of effector populations. Early phase studies using 'off-the shelf' universal donor CAR T cells have been undertaken mainly in the context of blood malignancies, where emerging data of clinical responses have supported wider adoption and further applications. These developments offer the prospect of alternatives to current autologous approaches through the emerging application of genome engineering solutions to improve safety, persistence and function of universal donor products.