Tethered IL-15 augments antitumor activity and promotes a stem-cell memory subset in tumor-specific T cells

Proc Natl Acad Sci U S A. 2016 Nov 29;113(48):E7788-E7797. doi: 10.1073/pnas.1610544113. Epub 2016 Nov 14.


Adoptive immunotherapy retargeting T cells to CD19 via a chimeric antigen receptor (CAR) is an investigational treatment capable of inducing complete tumor regression of B-cell malignancies when there is sustained survival of infused cells. T-memory stem cells (TSCM) retain superior potential for long-lived persistence, but challenges exist in manufacturing this T-cell subset because they are rare among circulating lymphocytes. We report a clinically relevant approach to generating CAR+ T cells with preserved TSCM potential using the Sleeping Beauty platform. Because IL-15 is fundamental to T-cell memory, we incorporated its costimulatory properties by coexpressing CAR with a membrane-bound chimeric IL-15 (mbIL15). The mbIL15-CAR T cells signaled through signal transducer and activator of transcription 5 to yield improved T-cell persistence independent of CAR signaling, without apparent autonomous growth or transformation, and achieved potent rejection of CD19+ leukemia. Long-lived T cells were CD45ROnegCCR7+CD95+, phenotypically most similar to TSCM, and possessed a memory-like transcriptional profile. Overall, these results demonstrate that CAR+ T cells can develop long-term persistence with a memory stem-cell phenotype sustained by signaling through mbIL15. This observation warrants evaluation in clinical trials.

Keywords: CAR; IL-15; T-cell persistence; T-memory stem cell; adoptive immunotherapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD19 / metabolism
  • Humans
  • Immunotherapy, Adoptive
  • Interleukin-15 / metabolism*
  • Lymphocyte Activation
  • Mice
  • Neoplasms, Experimental / therapy*
  • Precursor Cells, T-Lymphoid / physiology
  • Receptors, Antigen, T-Cell / metabolism*
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction
  • T-Lymphocyte Subsets / physiology*


  • Antigens, CD19
  • CD19 antigen, mouse
  • Interleukin-15
  • Receptors, Antigen, T-Cell
  • Recombinant Fusion Proteins