Clonal dynamics in vivo of virus integration sites of T cells expressing a safety switch

Edmund C. Chang, Hao Liu, John A. West, Xiaoou Zhou, Olga Dakhova, David A. Wheeler, Helen E. Heslop, Malcolm K. Brenner, Gianpietro Dotti

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Safety switches are becoming relevant for the clinical translation of T-cell-based immunotherapies. In patients receiving an allogeneic hematopoietic stem cell transplant, the inducible caspase-9 gene (iC9) safety switch expressed by donor-derived T lymphocytes efficiently controls acute graft versus host disease (GvHD). However, in vivo elimination of iC9-T cells by the chemical inducer of dimerization (CID) that activates the iC9 protein is incomplete. To study this effect, we characterized the clonal diversity and dynamics of vector insertion sites (VIS) in iC9-T cells pre- and post-CID administration in four patients who developed GvHD. We identified 3,203 VIS among four patients and followed their in vivo clonal dynamics up to 161 days post-CID. VIS were categorized by their proximity to host genome elements, gene associations, and cis-modulatory relationship to mapped promoters. We found that VIS are preferentially located near open chromatin and promoter regions; furthermore, there was no evidence for selection bias among VIS surviving the CID treatment. The majority of iC9-T cells with high normalized VIS copy number at the time of GvHD onset were eliminated by CID, while iC9-T cells detectable post-CID generally have low normalized VIS copy number. We propose that suboptimal iC9 transgene expression is responsible for the incomplete elimination of iC9-T cells and illustrate here by simple model how cis-modulatory influences of local genome context and T-cell receptor activation status at time of CID treatment contribute to stochastic sparing of iC9-T cells.

Original languageEnglish (US)
Pages (from-to)736-745
Number of pages10
JournalMolecular Therapy
Volume24
Issue number4
DOIs
StatePublished - Apr 1 2016
Externally publishedYes

Fingerprint

Virus Integration
Caspase 9
Dimerization
T-Lymphocytes
Safety
Graft vs Host Disease
Genes
Switch Genes
Genome
Selection Bias
Hematopoietic Stem Cells
T-Cell Antigen Receptor
Transgenes
Genetic Promoter Regions
Immunotherapy
Chromatin
Tissue Donors
Transplants
Gene Expression

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

Cite this

Chang, E. C., Liu, H., West, J. A., Zhou, X., Dakhova, O., Wheeler, D. A., ... Dotti, G. (2016). Clonal dynamics in vivo of virus integration sites of T cells expressing a safety switch. Molecular Therapy, 24(4), 736-745. https://doi.org/10.1038/mt.2015.217

Clonal dynamics in vivo of virus integration sites of T cells expressing a safety switch. / Chang, Edmund C.; Liu, Hao; West, John A.; Zhou, Xiaoou; Dakhova, Olga; Wheeler, David A.; Heslop, Helen E.; Brenner, Malcolm K.; Dotti, Gianpietro.

In: Molecular Therapy, Vol. 24, No. 4, 01.04.2016, p. 736-745.

Research output: Contribution to journalArticle

Chang, EC, Liu, H, West, JA, Zhou, X, Dakhova, O, Wheeler, DA, Heslop, HE, Brenner, MK & Dotti, G 2016, 'Clonal dynamics in vivo of virus integration sites of T cells expressing a safety switch', Molecular Therapy, vol. 24, no. 4, pp. 736-745. https://doi.org/10.1038/mt.2015.217
Chang, Edmund C. ; Liu, Hao ; West, John A. ; Zhou, Xiaoou ; Dakhova, Olga ; Wheeler, David A. ; Heslop, Helen E. ; Brenner, Malcolm K. ; Dotti, Gianpietro. / Clonal dynamics in vivo of virus integration sites of T cells expressing a safety switch. In: Molecular Therapy. 2016 ; Vol. 24, No. 4. pp. 736-745.
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