Genome-edited allogeneic donor universal chimeric antigen receptor T cells

alpha beta T cell receptor (TCR alpha beta) T cells modified to express chimeric antigen receptors (CAR), are now available as authorized therapies for certain B-cell malignancies. However the process of autologous harvest and generation of patient-specific products is costly, with complex logistics and infrastructure requirements. Premanufactured banks of allogeneic donor-derived CAR T cells could help widen applicability if the challenges of HLA-mismatched T-cell therapy can be addressed. Genome editing is being applied to overcome allogeneic barriers, most notably, by disrupting TCR alpha beta to prevent graft-versus-host disease, and multiple competing editing technologies, including CRISPR/Cas9 and base editing, have reached clinical phase testing. Improvements in accuracy and efficiency have unlocked applications for a wider range of blood malignancies, with multiplexed editing incorporated to target HLA molecules, shared antigens and checkpoint pathways. Clinical trials will help establish safety profiles and determine the durability of responses as well as the role of consolidation with allogeneic transplantation.

Automated summary

Genome editing technologies, such as CRISPR/Cas9, are being used to overcome the challenges of allogeneic T-cell therapy for blood malignancies by disrupting TCR alpha beta and preventing graft-versus-host disease. Premanufactured banks of allogeneic donor-derived CAR T cells could help address the complex logistics and high costs of autologous therapies, if HLA-mismatched T-cell therapy can be successfully addressed. Clinical trials will be crucial in determining the safety and efficacy of these modified T-cell therapies.