PMID- 27849617 OWN - NLM STAT- MEDLINE DCOM- 20180330 LR - 20210103 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 113 IP - 48 DP - 2016 Nov 29 TI - Tethered IL-15 augments antitumor activity and promotes a stem-cell memory subset in tumor-specific T cells. PG - E7788-E7797 AB - 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 (T(SCM)) 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 T(SCM) 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 CD45RO(neg)CCR7(+)CD95(+), phenotypically most similar to T(SCM), 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. FAU - Hurton, Lenka V AU - Hurton LV AD - Division of Pediatrics, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030. AD - The University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030. FAU - Singh, Harjeet AU - Singh H AD - Division of Pediatrics, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030. FAU - Najjar, Amer M AU - Najjar AM AD - Cancer Systems Imaging, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030. FAU - Switzer, Kirsten C AU - Switzer KC AD - Division of Pediatrics, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030. FAU - Mi, Tiejuan AU - Mi T AD - Division of Pediatrics, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030. FAU - Maiti, Sourindra AU - Maiti S AD - Division of Pediatrics, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030. FAU - Olivares, Simon AU - Olivares S AD - Division of Pediatrics, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030. FAU - Rabinovich, Brian AU - Rabinovich B AD - Division of Pediatrics, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030. FAU - Huls, Helen AU - Huls H AD - Division of Pediatrics, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030. AD - Intrexon, Germantown, MD 20876. FAU - Forget, Marie-Andree AU - Forget MA AD - Division of Pediatrics, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030. AD - Melanoma Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030. FAU - Datar, Vrushali AU - Datar V AD - Cancer Systems Imaging, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030. FAU - Kebriaei, Partow AU - Kebriaei P AD - Stem Cell Transplantation and Cellular Therapy, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030. FAU - Lee, Dean A AU - Lee DA AD - Division of Pediatrics, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030. FAU - Champlin, Richard E AU - Champlin RE AD - Stem Cell Transplantation and Cellular Therapy, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030. FAU - Cooper, Laurence J N AU - Cooper LJ AD - Division of Pediatrics, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030; ljncooper@mdanderson.org. AD - ZIOPHARM Oncology, Inc., Boston, MA 02129. LA - eng GR - R01 CA141303/CA/NCI NIH HHS/United States GR - P30 CA016672/CA/NCI NIH HHS/United States GR - R01 CA124782/CA/NCI NIH HHS/United States GR - P50 CA100632/CA/NCI NIH HHS/United States GR - P50 CA136411/CA/NCI NIH HHS/United States GR - P01 CA148600/CA/NCI NIH HHS/United States GR - R01 CA120956/CA/NCI NIH HHS/United States GR - TL1 TR000369/TR/NCATS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20161114 PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (Antigens, CD19) RN - 0 (CD19 antigen, mouse) RN - 0 (Interleukin-15) RN - 0 (Receptors, Antigen, T-Cell) RN - 0 (Recombinant Fusion Proteins) SB - IM CIN - Sci Transl Med. 2016 Dec 21;8(370):370ec205. PMID: 28003544 MH - Animals MH - Antigens, CD19/metabolism MH - Humans MH - Immunotherapy, Adoptive MH - Interleukin-15/*metabolism MH - Lymphocyte Activation MH - Mice MH - Neoplasms, Experimental/*therapy MH - Precursor Cells, T-Lymphoid/physiology MH - Receptors, Antigen, T-Cell/*metabolism MH - Recombinant Fusion Proteins/metabolism MH - Signal Transduction MH - T-Lymphocyte Subsets/*physiology PMC - PMC5137758 OTO - NOTNLM OT - CAR OT - IL-15 OT - T-cell persistence OT - T-memory stem cell OT - adoptive immunotherapy COIS- Some of the technology described was advanced through research conducted at the M. D. Anderson Cancer Center by L.J.N.C. The M. D. Anderson Cancer Center, L.J.N.C., L.V.H., K.C.S., H.S., T.M., S.M., S.O., B.R., M.-A.F., H.H., A.M.N., R.E.C., and D.A.L. all have or had a financial interest in ZIOPHARM Oncology, Inc., and Intrexon Corporation. On May 7, 2015, L.J.N.C. was appointed as the Chief Executive Officer at ZIOPHARM. L.J.N.C. is now a Visiting Scientist at the M. D. Anderson Cancer Center. A patent application based on this manuscript has been filed. EDAT- 2016/11/17 06:00 MHDA- 2018/03/31 06:00 PMCR- 2016/11/14 CRDT- 2016/11/17 06:00 PHST- 2016/11/17 06:00 [pubmed] PHST- 2018/03/31 06:00 [medline] PHST- 2016/11/17 06:00 [entrez] PHST- 2016/11/14 00:00 [pmc-release] AID - 1610544113 [pii] AID - 201610544 [pii] AID - 10.1073/pnas.1610544113 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2016 Nov 29;113(48):E7788-E7797. doi: 10.1073/pnas.1610544113. Epub 2016 Nov 14.