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
; 113(48): E7788-E7797, 2016 11 29.
Article
em En
| MEDLINE
| ID: mdl-27849617
ABSTRACT
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.
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MEDLINE
Assunto principal:
Receptores de Antígenos de Linfócitos T
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Subpopulações de Linfócitos T
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Interleucina-15
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Neoplasias Experimentais
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article