An inducible caspase 9 safety switch for T-cell therapy

Straathof, Karin; Pulé, Martin; Yotnda, Patricia; Dotti, Gianpietro; Vanin, Elio F.; Brenner, Malcolm K.; Heslop, Helen E.; Spencer, David M.; Rooney, Cliona M.

doi:10.1182/blood-2004-11-4564

Cited by 633 publications

(549 citation statements)

References 44 publications

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“…[19][20][21][22] Our approach allows patients to receive gancyclovir and related drugs to treat viral infections without T-cell damage. Unlike the HSV-tk-based suicide gene, the iC9 safety switch is human derived and has limited immunogenicity.…”

Section: Introductionmentioning

confidence: 99%

Inducible caspase-9 suicide gene controls adverse effects from alloreplete T cells after haploidentical stem cell transplantation

Zhou

Dotti

Krance

et al. 2015

Blood

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188

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• Alloreplete iC9-T cells can promote immune recovery posttransplant and protect patients against viral infections.• iC9-T cells can be eliminated from both peripheral blood and CNS by administration of AP1903 leading to a rapid resolution of GVHD.To test the feasibility of a single T-cell manipulation to eliminate alloreactivity while sparing antiviral and antitumor T cells, we infused 12 haploidentical hematopoietic stem cell transplant patients with increasing numbers of alloreplete haploidentical T cells expressing the inducible caspase 9 suicide gene (iC9-T cells). We determined whether the iC9-T cells produced immune reconstitution and if any resultant graft-versus-host disease (GVHD) could be controlled by administration of a chemical inducer of dimerization (CID; AP1903/ Rimiducid). All patients receiving >10 4 alloreplete iC9-T lymphocytes per kilogram achieved rapid reconstitution of immune responses toward 5 major pathogenic viruses and concomitant control of active infections. Four patients received a single AP1903 dose. CID infusion eliminated 85% to 95% of circulating CD3 1 CD19 1 T cells within 30 minutes, with no recurrence of GVHD within 90 days. In one patient, symptoms and signs of GVHDassociated cytokine release syndrome (CRS-hyperpyrexia, high levels of proinflammatory cytokines, and rash) resolved within 2 hours of AP1903 infusion. One patient with varicella zoster virus meningitis and acute GVHD had iC9-T cells present in the cerebrospinal fluid, which were reduced by >90% after CID. Notably, virus-specific T cells recovered even after AP1903 administration and continued to protect against infection. Hence, alloreplete iC9-T cells can reconstitute immunity posttransplant and administration of CID can eliminate them from both peripheral blood and the central nervous system (CNS), leading to rapid resolution of GVHD and CRS. The approach may therefore be useful for the rapid and effective treatment of toxicities associated with infusion of engineered T lymphocytes. This trial was registered at www.clinicaltrials.gov as #NCT01494103. (Blood. 2015;125(26):4103-4113)

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Section: Introductionmentioning

confidence: 99%

Inducible caspase-9 suicide gene controls adverse effects from alloreplete T cells after haploidentical stem cell transplantation

Zhou

Dotti

Krance

et al. 2015

Blood

Self Cite

188

172

View full text Add to dashboard Cite

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“…Approaches to improving CAR-T-cell safety have included the use of kill switches that can eliminate CAR-T cells in the case of severe toxicity (13,14). However, kill switches do not provide control over T-cell activation and expansion, and result in the irreversible elimination of potentially therapeutic CAR-T cells.…”

mentioning

confidence: 99%

Switch-mediated activation and retargeting of CAR-T cells for B-cell malignancies

Rodgers

Mazagova

Hampton

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

343

328

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Chimeric antigen receptor T (CAR-T) cell therapy has produced impressive results in clinical trials for B-cell malignancies. However, safety concerns related to the inability to control CAR-T cells once infused into the patient remain a significant challenge. Here we report the engineering of recombinant antibody-based bifunctional switches that consist of a tumor antigen-specific Fab molecule engrafted with a peptide neo-epitope, which is bound exclusively by a peptide-specific switchable CAR-T cell (sCAR-T). The switch redirects the activity of the bio-orthogonal sCAR-T cells through the selective formation of immunological synapses, in which the sCAR-T cell, switch, and target cell interact in a structurally defined and temporally controlled manner. Optimized switches specific for CD19 controlled the activity, tissue-homing, cytokine release, and phenotype of sCAR-T cells in a dose-titratable manner in a Nalm-6 xenograft rodent model of B-cell leukemia. The sCAR–T-cell dosing regimen could be tuned to provide efficacy comparable to the corresponding conventional CART-19, but with lower cytokine levels, thereby offering a method of mitigating cytokine release syndrome in clinical translation. Furthermore, we demonstrate that this methodology is readily adaptable to targeting CD20 on cancer cells using the same sCAR-T cell, suggesting that this approach may be broadly applicable to heterogeneous and resistant tumor populations, as well as other liquid and solid tumor antigens.

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“…58 This CAR also contains an iCaspase suicide safety switch that can be activated leading to programmed cell death to prevent unanticipated toxicities such as cytokine storm. 59,60 CAR T cell therapy directed against Her2/Neu has been used to target other pediatric solid tumors. The results of an ongoing phase I clinical trial in 19 patients with advanced pediatric sarcomas utilizing Her2/Neu-CAR T cells was recently published.…”

Section: Car T Cell Adoptive Cell Transfermentioning

confidence: 99%