The inducible caspase-9 suicide gene system as a 'safety switch' to limit on-target, off-tumor toxicities of chimeric antigen receptor T cells

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dc.contributor.authorGargett, T.
dc.contributor.authorBrown, M.
dc.date.issued2014
dc.descriptionPublished online: 28 October 2014.
dc.description.abstractImmune modulation has become a central element in many cancer treatments, and T cells genetically engineered to express chimeric antigen receptors (CAR) may provide a new approach to cancer immunotherapy. Autologous CAR T cells that have been re-directed toward tumor-associated antigens (TAA) have shown promising results in phase 1 clinical trials, with some patients undergoing complete tumor regression. However, this T-cell therapy must carefully balance effective T-cell activation, to ensure antitumor activity, with the potential for uncontrolled activation that may produce immunopathology. An inducible Caspase 9 (iCasp9) "safety switch" offers a solution that allows for the removal of inappropriately activated CAR T cells. The induction of iCasp9 depends on the administration of the small molecule dimerizer drug AP1903 and dimerization results in rapid induction of apoptosis in transduced cells, preferentially killing activated cells expressing high levels of transgene. The iCasp9 gene has been incorporated into vectors for use in preclinical studies and demonstrates effective and reliable suicide gene activity in phase 1 clinical trials. A third-generation CAR incorporating iCasp9 re-directs T cells toward the GD2 TAA. GD2 is over-expressed in melanoma and other malignancies of neural crest origin and the safety and activity of these GD2-iCAR T cells will be investigated in CARPETS and other actively recruiting phase 1 trials.
dc.description.statementofresponsibilityTessa Gargett and Michael P. Brown
dc.identifier.citationFrontiers in Pharmacology, 2014; 5(OCT):235-1-235-7
dc.identifier.doi10.3389/fphar.2014.00235
dc.identifier.issn1663-9812
dc.identifier.issn1663-9812
dc.identifier.orcidGargett, T. [0000-0003-3713-1373]
dc.identifier.orcidBrown, M. [0000-0002-5796-1932] [0000-0002-6678-1407]
dc.identifier.urihttp://hdl.handle.net/2440/91715
dc.language.isoen
dc.publisherFrontiers Research Foundation
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1010386
dc.rightsCopyright © 2014 Gargett and Brown. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
dc.source.urihttps://doi.org/10.3389/fphar.2014.00235
dc.subjectchimeric antigen receptor T cells; inducible caspase 9; AP1903; suicide gene; safety switch; cancer immunotherapy
dc.titleThe inducible caspase-9 suicide gene system as a 'safety switch' to limit on-target, off-tumor toxicities of chimeric antigen receptor T cells
dc.typeJournal article
pubs.publication-statusPublished

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