Regulated Expansion and Survival of Chimeric Antigen Receptor-Modified T Cells Using Small Molecule-Dependent Inducible MyD88/CD40

Aaron E. Foster, Aruna Mahendravada, Nicholas P. Shinners, Wei Chun Chang, Jeannette Crisostomo, An Lu, Mariam Khalil, Eva Morschl, Joanne L. Shaw, Sunandan Saha, My Linh T. Duong, Matthew R. Collinson-Pautz, David L. Torres, Tania Rodriguez, Tsvetelina Pentcheva-Hoang, J. Henri Bayle, Kevin M. Slawin, David M. Spencer

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37 Citations (Scopus)

Abstract

Anti-tumor efficacy of T cells engineered to express chimeric antigen receptors (CARs) is dependent on their specificity, survival, and in vivo expansion following adoptive transfer. Toll-like receptor (TLR) and CD40 signaling in T cells can improve persistence and drive proliferation of antigen-specific CD4+ and CD8+ T cells following pathogen challenge or in graft-versus-host disease (GvHD) settings, suggesting that these costimulatory pathways may be co-opted to improve CAR-T cell persistence and function. Here, we present a novel strategy to activate TLR and CD40 signaling in human T cells using inducible MyD88/CD40 (iMC), which can be triggered in vivo via the synthetic dimerizing ligand, rimiducid, to provide potent costimulation to CAR-modified T cells. Importantly, the concurrent activation of iMC (with rimiducid) and CAR (by antigen recognition) is required for interleukin (IL)-2 production and robust CAR-T cell expansion and may provide a user-controlled mechanism to amplify CAR-T cell levels in vivo and augment anti-tumor efficacy.

Original languageEnglish
Pages (from-to)2176-2188
Number of pages13
JournalMolecular Therapy
Volume25
Issue number9
DOIs
Publication statusPublished - Sep 6 2017

Keywords

  • CD40
  • MyD88
  • T cell
  • chimeric antigen receptor
  • costimulation
  • dimerizer
  • inducible

ASJC Scopus subject areas

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

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  • Cite this

    Foster, A. E., Mahendravada, A., Shinners, N. P., Chang, W. C., Crisostomo, J., Lu, A., Khalil, M., Morschl, E., Shaw, J. L., Saha, S., Duong, M. L. T., Collinson-Pautz, M. R., Torres, D. L., Rodriguez, T., Pentcheva-Hoang, T., Bayle, J. H., Slawin, K. M., & Spencer, D. M. (2017). Regulated Expansion and Survival of Chimeric Antigen Receptor-Modified T Cells Using Small Molecule-Dependent Inducible MyD88/CD40. Molecular Therapy, 25(9), 2176-2188. https://doi.org/10.1016/j.ymthe.2017.06.014