Adoptive T-cell therapy: adverse events and safety switches

Abstract

The potential of adoptive T-cell therapy in effecting complete and durable responses has been demonstrated in a number of malignant and infectious diseases. Ongoing progress in T-cell engineering has given cause for optimism in the broader clinical applicability of this approach. However, the development of more potent T cells is checked by safety concerns, highlighted by the occurrence of on-target and off-target toxicities that, although uncommon, have been fatal on occasions. Timely pharmacological intervention is effective in the management of a majority of adverse events but adoptively transferred T cells can persist long term, along with any unwanted effects. A recently validated cellular safety switch, inducible caspase 9 (iCasp9), has the potential to mitigate the risks of T-cell therapy by enabling the elimination of transferred T cells if required. In haematopoietic stem cell transplantation, iCasp9-modified donor T cells can be rapidly eliminated in the event of graft-versus-host disease. This review presents an overview of the risks associated with modern T-cell therapy and the development, clinical results and potential future application of the iCasp9 safety switch.

Figure 1

(a) The iCasp9 molecule consists of a drug-binding domain, FK506-F36V, joined, via a short linker, to ΔCaspase 9, which is caspase 9 without its physiological caspase recruitment domain (CARD). Binding of a small molecule dimeriser, AP1903, results in the dimerisation of ΔCaspase 9 that activates downstream effector caspases, leading to apoptosis. (b) The iCaps9.2A.ΔCD19 retroviral insert consists of iCasp9, joined via a 2A-like sequence, to ΔCD19, which serves as a surface selectable marker.