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Adoptive T-cell therapy: adverse events and safety switches.

Tey SK - Clin Transl Immunology (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Bone Marrow Transplant Laboratory, QIMR Berghofer Medical Research Institute , Brisbane, Queensland, Australia ; Department of Haematology and Bone Marrow Transplantation, Royal Brisbane and Women's Hospital , Brisbane, Queensland, Australia ; School of Medicine, University of Queensland , Brisbane, Queensland, Australia.

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.

No MeSH data available.


Related in: MedlinePlus

(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.
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fig1: (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.

Mentions: The optimised iCasp9 molecule consists of an FKBP12-F36V domain linked, via a flexible Ser-Gly-Gly-Gly-Ser linker, to a caspase 9 molecule, without the caspase activation and recruitment domain (CARD) (Figure 1a).54 CARD is the physiological dimerisation domain and is now superfluous. The iCasp9 has a good balance of low dimeriser-independent basal activity and high sensitivity to dimeriser-induced apoptosis. A single 10 nM dose of the dimeric FK506 analogue, AP1903 or AP20187, induces apoptosis within hours in >99% of cells that express high levels of iCasp9. T cells that express low or intermediate levels of iCasp9 are also susceptible to dimeriser-induced killing but to a lesser degree.54


Adoptive T-cell therapy: adverse events and safety switches.

Tey SK - Clin Transl Immunology (2014)

(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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4232067&req=5

fig1: (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.
Mentions: The optimised iCasp9 molecule consists of an FKBP12-F36V domain linked, via a flexible Ser-Gly-Gly-Gly-Ser linker, to a caspase 9 molecule, without the caspase activation and recruitment domain (CARD) (Figure 1a).54 CARD is the physiological dimerisation domain and is now superfluous. The iCasp9 has a good balance of low dimeriser-independent basal activity and high sensitivity to dimeriser-induced apoptosis. A single 10 nM dose of the dimeric FK506 analogue, AP1903 or AP20187, induces apoptosis within hours in >99% of cells that express high levels of iCasp9. T cells that express low or intermediate levels of iCasp9 are also susceptible to dimeriser-induced killing but to a lesser degree.54

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Bone Marrow Transplant Laboratory, QIMR Berghofer Medical Research Institute , Brisbane, Queensland, Australia ; Department of Haematology and Bone Marrow Transplantation, Royal Brisbane and Women's Hospital , Brisbane, Queensland, Australia ; School of Medicine, University of Queensland , Brisbane, Queensland, Australia.

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.

No MeSH data available.


Related in: MedlinePlus