Two-Dimensional Regulation of CAR-T Cell Therapy with Orthogonal Switches

My Linh T. Duong, Matthew R. Collinson-Pautz, Eva Morschl, An Lu, Slawomir P. Szymanski, Ming Zhang, Mary E. Brandt, Wei Chun Chang, Kelly L. Sharp, Steven M. Toler, Kevin M. Slawin, Aaron E. Foster, David M. Spencer, J. Henri Bayle

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Use of chimeric antigen receptors (CARs) as the basis of targeted adoptive T cell therapies has enabled dramatic efficacy against multiple hematopoietic malignancies, but potency against bulky and solid tumors has lagged, potentially due to insufficient CAR-T cell expansion and persistence. To improve CAR-T cell efficacy, we utilized a potent activation switch based on rimiducid-inducible MyD88 and CD40 (iMC)-signaling elements. To offset potential toxicity risks by this enhanced CAR, an orthogonally regulated, rapamycin-induced, caspase-9-based safety switch (iRC9) was developed to allow in vivo elimination of CAR-T cells. iMC costimulation induced by systemic rimiducid administration enhanced CAR-T cell proliferation, cytokine secretion, and antitumor efficacy in both in vitro assays and xenograft tumor models. Conversely, rapamycin-mediated iRC9 dimerization rapidly induced apoptosis in a dose-dependent fashion as an approach to mitigate therapy-related toxicity. This novel, regulatable dual-switch system may promote greater CAR-T cell expansion and prolonged persistence in a drug-dependent manner while providing a safety switch to mitigate toxicity concerns.

Original languageEnglish
Pages (from-to)124-137
Number of pages14
JournalMolecular Therapy - Oncolytics
Volume12
DOIs
Publication statusPublished - Mar 29 2019

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Keywords

  • CAR-T
  • apoptosis
  • cell therapy
  • costimulation switch
  • dimerizer
  • iMC
  • iRC9
  • rapamycin
  • rimiducid
  • safety switch

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Cancer Research
  • Pharmacology (medical)

Cite this

Duong, M. L. T., Collinson-Pautz, M. R., Morschl, E., Lu, A., Szymanski, S. P., Zhang, M., Brandt, M. E., Chang, W. C., Sharp, K. L., Toler, S. M., Slawin, K. M., Foster, A. E., Spencer, D. M., & Bayle, J. H. (2019). Two-Dimensional Regulation of CAR-T Cell Therapy with Orthogonal Switches. Molecular Therapy - Oncolytics, 12, 124-137. https://doi.org/10.1016/j.omto.2018.12.009