PMID- 27378343 OWN - NLM STAT- MEDLINE DCOM- 20170802 LR - 20190811 IS - 1477-2566 (Electronic) IS - 1465-3249 (Print) IS - 1465-3249 (Linking) VI - 18 IP - 8 DP - 2016 Aug TI - PR1-specific cytotoxic T lymphocytes are relatively frequent in umbilical cord blood and can be effectively expanded to target myeloid leukemia. PG - 995-1001 LID - S1465-3249(16)30381-4 [pii] LID - 10.1016/j.jcyt.2016.05.007 [doi] AB - BACKGROUND AIMS: PR1 is an HLA-A2 restricted leukemia-associated antigen derived from neutrophil elastase and proteinase 3, both of which are normally stored in the azurophil granules of myeloid cells but overexpressed in myeloid leukemic cells. PR1-specific cytotoxic lymphocytes (PR1-CTLs) have activity against primary myeloid leukemia in vitro and in vivo and thus could have great potential in the setting of adoptive cellular therapy (ACT). Adult peripheral blood-derived PR1-CTLs are infrequent but preferentially lyse myeloid leukemia cells. We sought to examine PR1-CTLs in umbilical cord blood (UCB) because UCB units provide a rapidly available cell source and a lower risk of graft-versus-host disease, even in the setting of mismatched human leukocyte antigen (HLA) loci. METHODS: We first determined the frequency of PR1-CTLs in HLA-A2(+) UCB units and then successfully expanded them ex vivo using repeated stimulation with PR1 peptide-pulsed antigen-presenting cells (APCs). After expansion, we assessed the PR1-CTL phenotype (naive, effector, memory) and function against PR1-expressing target cells. RESULTS: PR1-CTLs are detected at an average frequency of 0.14% within the CD8(+) population of fresh UCB units, which is 45 times higher than in healthy adult peripheral blood. UCB PR1-CTLs are phenotypically naive, consistent with the UCB CD8(+) population as a whole. In addition, the cells can be expanded by stimulation with PR1 peptide-pulsed APCs. Expansion results in an increased frequency of PR1-CTLs, up to 4.56%, with an average 20-fold increase in total number. After expansion, UCB PR1-CTLs express markers consistent with effector memory T cells. Expanded UCB PR1-CTLs are functional in vitro as they are able to produce cytokines and lyse PR1-expressing leukemia cell lines. CONCLUSIONS: This study is the first report to show that T cells specific for a leukemia-associated antigen are found at a significantly higher frequency in UCB than adult blood. Our results also demonstrate specific cytotoxicity of expanded UCB-derived PR1-CTLs against PR1-expressing targets. Together, our data suggest that UCB PR1-CTLs could be useful to prevent or treat leukemia relapse in myeloid leukemia patients. CI - Copyright (c) 2016 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved. FAU - St John, Lisa S AU - St John LS AD - Section of Transplantation Immunology, Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA. FAU - Wan, Liping AU - Wan L AD - Department of Hematology, Shanghai Jiao Tong University Affiliated First People's Hospital, Shanghai, China. FAU - He, Hong AU - He H AD - Section of Transplantation Immunology, Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA. FAU - Garber, Haven R AU - Garber HR AD - Section of Transplantation Immunology, Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA. FAU - Clise-Dwyer, Karen AU - Clise-Dwyer K AD - Section of Transplantation Immunology, Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA. FAU - Alatrash, Gheath AU - Alatrash G AD - Section of Transplantation Immunology, Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA. FAU - Rezvani, Katayoun AU - Rezvani K AD - Section of Transplantation Immunology, Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA. FAU - Shpall, Elizabeth J AU - Shpall EJ AD - Section of Transplantation Immunology, Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA. FAU - Bollard, Catherine M AU - Bollard CM AD - Center for Cancer and Immunology Research, Children's Research Institute, Washington, DC, USA. FAU - Ma, Qing AU - Ma Q AD - Section of Transplantation Immunology, Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA. FAU - Molldrem, Jeffrey J AU - Molldrem JJ AD - Section of Transplantation Immunology, Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA. Electronic address: jmolldre@mdanderson.org. LA - eng GR - P01 CA148600/CA/NCI NIH HHS/United States GR - P30 CA016672/CA/NCI NIH HHS/United States GR - P50 CA100632/CA/NCI NIH HHS/United States PT - Journal Article PL - England TA - Cytotherapy JT - Cytotherapy JID - 100895309 RN - 0 (HLA-A2 Antigen) RN - EC 3.4.21.76 (Myeloblastin) SB - IM CIN - Cytotherapy. 2016 Aug;18(8):929-930. PMID: 27378341 MH - Adult MH - *Antibody-Dependent Cell Cytotoxicity MH - Cells, Cultured MH - Fetal Blood/*cytology/immunology MH - HLA-A2 Antigen/chemistry/*immunology/metabolism MH - Humans MH - *Immunotherapy, Adoptive MH - K562 Cells MH - Leukemia, Myeloid/immunology/*therapy MH - Lymphocyte Count MH - Myeloblastin/chemistry/*immunology/metabolism MH - T-Lymphocytes, Cytotoxic/*immunology/metabolism MH - U937 Cells PMC - PMC4934389 MID - NIHMS786575 OTO - NOTNLM OT - PR1 OT - antigen specific cytotoxic T lymphocyte OT - leukemia OT - umbilical cord blood COIS- We have no conflict of interests. EDAT- 2016/07/06 06:00 MHDA- 2017/08/03 06:00 PMCR- 2017/08/01 CRDT- 2016/07/06 06:00 PHST- 2016/05/10 00:00 [received] PHST- 2016/05/11 00:00 [accepted] PHST- 2016/07/06 06:00 [entrez] PHST- 2016/07/06 06:00 [pubmed] PHST- 2017/08/03 06:00 [medline] PHST- 2017/08/01 00:00 [pmc-release] AID - S1465-3249(16)30381-4 [pii] AID - 10.1016/j.jcyt.2016.05.007 [doi] PST - ppublish SO - Cytotherapy. 2016 Aug;18(8):995-1001. doi: 10.1016/j.jcyt.2016.05.007.