Control of the antitumour activity and specificity of CAR T cells via organic adapters covalently tethering the CAR to tumour cells
Chimeric antigen receptor T cell (CAR-T cells) therapy has gained much attention in recent years owing to its well-recognized success in treating adults and children with B-cell malignancies. Very often CAR therapy can deliver considerable remission rates, and it has the potential to become part of standard-of-care treatment for acute lymphoblastic leukemia (ALL). However, current CAR-T cell therapy is still hampered by a variety of drawbacks. On-target off- tumour toxicity limits the anticancer applicability of chimaeric antigen receptor (CAR) T cells for solid tumours. One of the most troubling issues concerns the frequent induction of Cytokine Release Syndrome (CRS) resulted from overactivation of the T cells and on-target off-tumour effects. CAR therapy involves the injection of living cells with the capacity for replication. Unlike the usual side effects with pharmaceuticals that can be ameliorated by withholding drugs, or reducing dosage, CAR-T is much more difficult to regulate once it is initiated. Incorporating a safety switch for the CAR-T cells will lead to the development of safer immunotherapies. Here we show that the tumour-targeting specificity and activity of T cells with a CAR consisting of an antibody with a lysine residue that catalytically forms a reversible covalent bond with a 1,3-diketone hapten can be regulated by the concentration of a small-molecule adapter that selectively binds to the hapten and to a chosen tumour antigen via a small-molecule binder identified via a DNA-encoded library. The adapter therefore controls the formation of a covalent bond between the catalytic antibody and the hapten and the tethering of the CAR T cells to the tumour cells, and hence the cytotoxicity and specificity of the cytotoxic T cells, as we show in vitro and in mice with prostate cancer xenografts. Such small-molecule switches of T-cell cytotoxicity and specificity via an antigen-independent ‘universal’ CAR may enhance the control and safety profile of CAR-based cellular immunotherapies.
october 21, 2023