title: Tethered IL-15 augments antitumor activity and promotes a stem-cell memory subset in tumor-specific T cells.
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 TSCMpotential 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.
authors.affiliation: Division of Pediatrics, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030.|The University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030.
authors.forename: Lenka V
authors.initials: LV
authors.lastname: Hurton
authors.affiliation: Division of Pediatrics, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030.
authors.forename: Harjeet
authors.initials: H
authors.lastname: Singh
authors.affiliation: Cancer Systems Imaging, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030.
authors.forename: Amer M
authors.initials: AM
authors.lastname: Najjar
authors.affiliation: Division of Pediatrics, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030.
authors.forename: Kirsten C
authors.initials: KC
authors.lastname: Switzer
authors.affiliation: Division of Pediatrics, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030.
authors.forename: Tiejuan
authors.initials: T
authors.lastname: Mi
authors.affiliation: Division of Pediatrics, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030.
authors.forename: Sourindra
authors.initials: S
authors.lastname: Maiti
authors.affiliation: Division of Pediatrics, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030.
authors.forename: Simon
authors.initials: S
authors.lastname: Olivares
authors.affiliation: Division of Pediatrics, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030.
authors.forename: Brian
authors.initials: B
authors.lastname: Rabinovich
authors.affiliation: Division of Pediatrics, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030.|Intrexon, Germantown, MD 20876.
authors.forename: Helen
authors.initials: H
authors.lastname: Huls
authors.affiliation: Division of Pediatrics, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030.|Melanoma Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030.
authors.forename: Marie-Andrée
authors.initials: MA
authors.lastname: Forget
authors.affiliation: Cancer Systems Imaging, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030.
authors.forename: Vrushali
authors.initials: V
authors.lastname: Datar
authors.affiliation: Stem Cell Transplantation and Cellular Therapy, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030.
authors.forename: Partow
authors.initials: P
authors.lastname: Kebriaei
authors.affiliation: Division of Pediatrics, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030.
authors.forename: Dean A
authors.initials: DA
authors.lastname: Lee
authors.affiliation: Stem Cell Transplantation and Cellular Therapy, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Champlin
authors.affiliation: Division of Pediatrics, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030; ljncooper@mdanderson.org.|ZIOPHARM Oncology, Inc., Boston, MA 02129.
authors.forename: Laurence J N
authors.initials: LJ
authors.lastname: Cooper
mesh_terms: D000818:Animals; D018941:Antigens, CD19 / Q000378:metabolism; D006801:Humans; D016219:Immunotherapy, Adoptive; D019409:Interleukin-15 / Q000378:metabolism*; D008213:Lymphocyte Activation; D051379:Mice; D009374:Neoplasms, Experimental / Q000628:therapy*; D054504:Precursor Cells, T-Lymphoid / Q000502:physiology; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000502:physiology*
chemical_list: D018941:Antigens, CD19; C000604812:CD19 antigen, mouse; D019409:Interleukin-15; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins
keywords: CAR; IL-15; T-cell persistence; T-memory stem cell; adoptive immunotherapy