{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,13]],"date-time":"2026-11-13T13:26:36Z","timestamp":1794576396191,"version":"4.9.1"},"reference-count":51,"publisher":"American Society of Hematology","issue":"3","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2018,2,13]]},"abstract":"<jats:title>Key Points<\/jats:title><jats:p>Number of prior chemotherapy cycles in cancer patients correlates with T-cell senescent phenotype and loss of CD27 and CD28 expression. Addition of PI3K\u03b4 inhibitors and VIP antagonists increased ex vivo expansion, in vivo persistence, and anticancer cytotoxicity of T cells.<\/jats:p>","DOI":"10.1182\/bloodadvances.2017011254","type":"journal-article","created":{"date-parts":[[2018,2,1]],"date-time":"2018-02-01T01:35:13Z","timestamp":1517448913000},"page":"210-223","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":109,"title":["Improving T-cell expansion and function for adoptive T-cell therapy using ex vivo treatment with PI3K\u03b4 inhibitors and VIP antagonists"],"prefix":"10.1182","volume":"2","author":[{"given":"Christopher T.","family":"Petersen","sequence":"first","affiliation":[{"name":"Department of Hematology and Oncology, Emory University School of Medicine, Atlanta, GA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mojibade","family":"Hassan","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Emory University School of Medicine, Atlanta, GA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna B.","family":"Morris","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Emory University School of Medicine, Atlanta, GA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasmin","family":"Jeffery","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Emory University School of Medicine, Atlanta, GA;"},{"name":"Department of Chemistry, Hampton University, Hampton, VA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kunhee","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Emory University School of Medicine, Atlanta, GA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neera","family":"Jagirdar","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Emory University School of Medicine, Atlanta, GA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley D.","family":"Staton","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Emory University School of Medicine, Atlanta, GA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunil S.","family":"Raikar","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Emory University School of Medicine, Atlanta, GA; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harold T.","family":"Spencer","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Emory University School of Medicine, Atlanta, GA; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Todd","family":"Sulchek","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher R.","family":"Flowers","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Emory University School of Medicine, Atlanta, GA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0816-6729","authenticated-orcid":false,"given":"Edmund K.","family":"Waller","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Emory University School of Medicine, Atlanta, GA;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","published-online":{"date-parts":[[2018,1,31]]},"reference":[{"issue":"177","key":"2019111616104359100_B1","doi-asserted-by":"crossref","first-page":"177ra38","DOI":"10.1126\/scitranslmed.3005930","article-title":"CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia","volume":"5","author":"Brentjens","year":"2013","journal-title":"Sci Transl Med"},{"issue":"2","key":"2019111616104359100_B2","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.critrevonc.2012.12.009","article-title":"Diffuse large B-cell lymphoma","volume":"87","author":"Martelli","year":"2013","journal-title":"Crit Rev Oncol Hematol"},{"issue":"1","key":"2019111616104359100_B3","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/j.ymthe.2016.10.020","article-title":"Phase 1 Results of ZUMA-1: A Multicenter Study of KTE-C19 Anti-CD19 CAR T Cell Therapy in Refractory Aggressive Lymphoma","volume":"25","author":"Locke","year":"2017","journal-title":"Mol Ther"},{"issue":"1","key":"2019111616104359100_B4","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1634\/stemcells.18-1-10","article-title":"T-cell immunodeficiency following cytotoxic antineoplastic therapy: a review","volume":"18","author":"Mackall","year":"2000","journal-title":"Stem Cells"},{"issue":"1","key":"2019111616104359100_B5","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1172\/JCI81217","article-title":"Memory T cell-driven differentiation of naive cells impairs adoptive immunotherapy","volume":"126","author":"Klebanoff","year":"2016","journal-title":"J Clin Invest"},{"key":"2019111616104359100_B6","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1002\/hon.2437_6","article-title":"Global pivotal phase 2 trial of the CD19-targeted therapy CTL019 in adult patients with relapsed or refractory (R\/R) diffuse large B-cell lymphoma (DLBCL)\u2014an interim analysis","volume":"35","author":"Schuster","year":"2017","journal-title":"Hematol Oncol"},{"key":"2019111616104359100_B7","doi-asserted-by":"crossref","DOI":"10.1182\/blood.V126.23.183.183","article-title":"Sustained remissions following chimeric antigen receptor modified t cells directed against CD19 (CTL019) in patients with relapsed or refractory CD19+ lymphomas","author":"Schuster","year":"2015"},{"issue":"4","key":"2019111616104359100_B8","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1182\/blood-2005-08-3373","article-title":"A phase 1 trial of donor lymphocyte infusions expanded and activated ex vivo via CD3\/CD28 costimulation","volume":"107","author":"Porter","year":"2006","journal-title":"Blood"},{"issue":"1","key":"2019111616104359100_B9","doi-asserted-by":"crossref","first-page":"348","DOI":"10.4049\/jimmunol.1601494","article-title":"Comprehensive approach for identifying the T cell subset origin of CD3 and CD28 antibody-activated chimeric antigen receptor-modified T cells","volume":"199","author":"Schmueck-Henneresse","year":"2017","journal-title":"J Immunol"},{"issue":"11","key":"2019111616104359100_B10","doi-asserted-by":"crossref","first-page":"e15423","DOI":"10.1371\/journal.pone.0015423","article-title":"The cell cycle time of CD8+ T cells responding in vivo is controlled by the type of antigenic stimulus","volume":"5","author":"Yoon","year":"2010","journal-title":"PLoS One"},{"issue":"12","key":"2019111616104359100_B11","doi-asserted-by":"crossref","first-page":"2347","DOI":"10.1182\/blood-2012-06-437640","article-title":"Pharmacological inhibition of VIP signaling enhances antiviral immunity and improves survival in murine cytomegalovirus-infected allogeneic bone marrow transplant recipients","volume":"121","author":"Li","year":"2013","journal-title":"Blood"},{"issue":"5","key":"2019111616104359100_B12","doi-asserted-by":"crossref","first-page":"e63381","DOI":"10.1371\/journal.pone.0063381","article-title":"VIPhyb, an antagonist of vasoactive intestinal peptide receptor, enhances cellular antiviral immunity in murine cytomegalovirus infected mice","volume":"8","author":"Li","year":"2013","journal-title":"PLoS One"},{"issue":"23","key":"2019111616104359100_B13","doi-asserted-by":"crossref","first-page":"6802","DOI":"10.1158\/0008-5472.CAN-16-0427","article-title":"Modulation of immune checkpoints and graft-versus-leukemia in allogeneic transplants by antagonizing vasoactive intestinal peptide signaling","volume":"76","author":"Li","year":"2016","journal-title":"Cancer Res"},{"issue":"5","key":"2019111616104359100_B14","doi-asserted-by":"crossref","first-page":"e1304336","DOI":"10.1080\/2162402X.2017.1304336","article-title":"Administration of a vasoactive intestinal peptide antagonist enhances the autologous anti-leukemia T cell response in murine models of acute leukemia","volume":"6","author":"Petersen","year":"2017","journal-title":"OncoImmunology"},{"issue":"2","key":"2019111616104359100_B15","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1182\/blood-2016-03-707133","article-title":"Idelalisib given front-line for treatment of chronic lymphocytic leukemia causes frequent immune-mediated hepatotoxicity","volume":"128","author":"Lampson","year":"2016","journal-title":"Blood"},{"issue":"2","key":"2019111616104359100_B16","doi-asserted-by":"crossref","first-page":"233","DOI":"10.20524\/aog.2016.0022","article-title":"Idelalisib: a rare cause of enterocolitis","volume":"29","author":"Balagoni","year":"2016","journal-title":"Ann Gastroenterol"},{"issue":"12","key":"2019111616104359100_B17","doi-asserted-by":"crossref","first-page":"1653","DOI":"10.1097\/PAS.0000000000000525","article-title":"Idelalisib-associated enterocolitis: clinicopathologic features and distinction from other enterocolitides","volume":"39","author":"Louie","year":"2015","journal-title":"Am J Surg Pathol"},{"issue":"1","key":"2019111616104359100_B18","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/1074-7613(95)90161-2","article-title":"CD28 costimulation can promote T cell survival by enhancing the expression of Bcl-XL","volume":"3","author":"Boise","year":"1995","journal-title":"Immunity"},{"issue":"2","key":"2019111616104359100_B19","doi-asserted-by":"crossref","first-page":"636","DOI":"10.4049\/jimmunol.157.2.636","article-title":"CD28 costimulation prevents cell death during primary T cell activation","volume":"157","author":"Noel","year":"1996","journal-title":"J Immunol"},{"issue":"12","key":"2019111616104359100_B20","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1038\/nri1248","article-title":"CD28-mediated co-stimulation: a quantitative support for TCR signalling","volume":"3","author":"Acuto","year":"2003","journal-title":"Nat Rev Immunol"},{"issue":"6","key":"2019111616104359100_B21","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1093\/protein\/7.6.805","article-title":"Human-engineered monoclonal antibodies retain full specific binding activity by preserving non-CDR complementarity-modulating residues","volume":"7","author":"Studnicka","year":"1994","journal-title":"Protein Eng"},{"key":"2019111616104359100_B22","doi-asserted-by":"crossref","first-page":"16026","DOI":"10.1038\/mto.2016.26","article-title":"Genetic engineering of chimeric antigen receptors using lamprey derived variable lymphocyte receptors","volume":"3","author":"Moot","year":"2016","journal-title":"Mol Ther Oncolytics"},{"issue":"1","key":"2019111616104359100_B23","first-page":"141","article-title":"Different mechanisms for anti-tumor effects of low- and high-dose cyclophosphamide","volume":"16","author":"Motoyoshi","year":"2006","journal-title":"Oncol Rep"},{"issue":"7","key":"2019111616104359100_B24","doi-asserted-by":"crossref","first-page":"2221","DOI":"10.1182\/blood.V84.7.2221.2221","article-title":"Lymphocyte depletion during treatment with intensive chemotherapy for cancer","volume":"84","author":"Mackall","year":"1994","journal-title":"Blood"},{"issue":"3","key":"2019111616104359100_B25","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1056\/NEJM199501193320303","article-title":"Age, thymopoiesis, and CD4+ T-lymphocyte regeneration after intensive chemotherapy","volume":"332","author":"Mackall","year":"1995","journal-title":"N Engl J Med"},{"issue":"2","key":"2019111616104359100_B26","first-page":"117","article-title":"An interim analysis of the ZUMA-1 study of KTE-C19 in refractory, aggressive non-Hodgkin lymphoma","volume":"15","author":"Neelapu","year":"2017","journal-title":"Clin Adv Hematol Oncol"},{"issue":"9","key":"2019111616104359100_B27","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.1016\/S0301-472X(99)00083-1","article-title":"Analysis of T-cell defects in the specific immune response against acute lymphoblastic leukemia cells","volume":"27","author":"Yotnda","year":"1999","journal-title":"Exp Hematol"},{"issue":"10","key":"2019111616104359100_B28","doi-asserted-by":"crossref","first-page":"3700","DOI":"10.1182\/blood.V89.10.3700","article-title":"Distinctions between CD8+ and CD4+ T-cell regenerative pathways result in prolonged T-cell subset imbalance after intensive chemotherapy","volume":"89","author":"Mackall","year":"1997","journal-title":"Blood"},{"issue":"1","key":"2019111616104359100_B29","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/1742-4933-5-6","article-title":"Multiparameter flow cytometric analysis of CD4 and CD8 T cell subsets in young and old people","volume":"5","author":"Koch","year":"2008","journal-title":"Immun Ageing"},{"issue":"1","key":"2019111616104359100_B30","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1002\/cyto.a.22351","article-title":"From \u201ctruly na\u00efve\u201d to \u201cexhausted senescent\u201d T cells: when markers predict functionality","volume":"85","author":"Larbi","year":"2014","journal-title":"Cytometry A"},{"issue":"9","key":"2019111616104359100_B31","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1038\/nrc.2016.97","article-title":"Engineered T cells: the promise and challenges of cancer immunotherapy","volume":"16","author":"Fesnak","year":"2016","journal-title":"Nat Rev Cancer"},{"issue":"1","key":"2019111616104359100_B32","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1146\/annurev.immunol.21.120601.141110","article-title":"T cell anergy","volume":"21","author":"Schwartz","year":"2003","journal-title":"Annu Rev Immunol"},{"issue":"2","key":"2019111616104359100_B33","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1177\/2040620715625966","article-title":"The role of idelalisib in the treatment of relapsed and refractory chronic lymphocytic leukemia","volume":"7","author":"Nair","year":"2016","journal-title":"Ther Adv Hematol"},{"key":"2019111616104359100_B34","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.biocel.2017.02.007","article-title":"Anti-tumor activity of PI3K-\u03b4 inhibitor in hematologic malignant cells: shedding new light on resistance to Idelalisib","volume":"85","author":"Bashash","year":"2017","journal-title":"Int J Biochem Cell Biol"},{"issue":"2","key":"2019111616104359100_B35","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1053\/j.seminoncol.2016.02.004","article-title":"The PI3K pathway: clinical inhibition in chronic lymphocytic leukemia","volume":"43","author":"Brown","year":"2016","journal-title":"Semin Oncol"},{"issue":"3","key":"2019111616104359100_B36","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1038\/nri2036","article-title":"PI3K delta and PI3K gamma: partners in crime in inflammation in rheumatoid arthritis and beyond?","volume":"7","author":"Rommel","year":"2007","journal-title":"Nat Rev Immunol"},{"issue":"7","key":"2019111616104359100_B37","doi-asserted-by":"crossref","first-page":"3206","DOI":"10.4049\/jimmunol.1501227","article-title":"PI3K\u03b4 Regulates the Magnitude of CD8+ T Cell Responses after Challenge with Listeria monocytogenes","volume":"195","author":"Pearce","year":"2015","journal-title":"J Immunol"},{"issue":"7613","key":"2019111616104359100_B38","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1038\/nature17641","article-title":"Corrigendum: Inactivation of PI(3)K p110\u03b4 breaks regulatory T-cell-mediated immune tolerance to cancer","volume":"535","author":"Ali","year":"2016","journal-title":"Nature"},{"issue":"6","key":"2019111616104359100_B39","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1038\/ni.2035","article-title":"T cell exhaustion","volume":"12","author":"Wherry","year":"2011","journal-title":"Nat Immunol"},{"issue":"4","key":"2019111616104359100_B40","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1038\/nri1056","article-title":"PI3K in lymphocyte development, differentiation and activation","volume":"3","author":"Okkenhaug","year":"2003","journal-title":"Nat Rev Immunol"},{"issue":"1","key":"2019111616104359100_B41","doi-asserted-by":"crossref","first-page":"73","DOI":"10.4196\/kjpp.2014.18.1.73","article-title":"Bcl-2 knockdown accelerates T cell receptor-triggered activation-induced cell death in jurkat T cells","volume":"18","author":"Lee","year":"2014","journal-title":"Korean J Physiol Pharmacol"},{"issue":"2","key":"2019111616104359100_B42","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1124\/pr.56.2.7","article-title":"The significance of vasoactive intestinal peptide in immunomodulation","volume":"56","author":"Delgado","year":"2004","journal-title":"Pharmacol Rev"},{"issue":"1","key":"2019111616104359100_B43","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1007\/s00726-011-1184-8","article-title":"Vasoactive intestinal peptide: a neuropeptide with pleiotropic immune functions","volume":"45","author":"Delgado","year":"2013","journal-title":"Amino Acids"},{"issue":"1","key":"2019111616104359100_B44","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1002\/jnr.490290104","article-title":"Inhibition of mouse T-cell proliferation by CGRP and VIP: effects of these neuropeptides on IL-2 production and cAMP synthesis","volume":"29","author":"Boudard","year":"1991","journal-title":"J Neurosci Res"},{"issue":"1-3","key":"2019111616104359100_B45","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/S0167-0115(99)00068-3","article-title":"Vasoactive intestinal peptide inhibits cytokine production in T lymphocytes through cAMP-dependent and cAMP-independent mechanisms","volume":"84","author":"Wang","year":"1999","journal-title":"Regul Pept"},{"issue":"1","key":"2019111616104359100_B46","doi-asserted-by":"crossref","first-page":"114","DOI":"10.4049\/jimmunol.165.1.114","article-title":"Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit T cell-mediated cytotoxicity by inhibiting Fas ligand expression","volume":"165","author":"Delgado","year":"2000","journal-title":"J Immunol"},{"issue":"10","key":"2019111616104359100_B47","doi-asserted-by":"crossref","first-page":"2537","DOI":"10.1128\/MCB.01282-09","article-title":"Vasoactive intestinal peptide induces cell cycle arrest and regulatory functions in human T cells at multiple levels","volume":"30","author":"Anderson","year":"2010","journal-title":"Mol Cell Biol"},{"issue":"6","key":"2019111616104359100_B48","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1189\/jlb.0605299","article-title":"Vasoactive intestinal peptide generates CD4+CD25+ regulatory T cells in vivo","volume":"78","author":"Delgado","year":"2005","journal-title":"J Leukoc Biol"},{"issue":"1","key":"2019111616104359100_B49","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/S0022-3565(25)24227-6","article-title":"Substance P and vasoactive intestinal peptide degradation by mast cell tryptase and chymase","volume":"244","author":"Caughey","year":"1988","journal-title":"J Pharmacol Exp Ther"},{"issue":"45","key":"2019111616104359100_B50","doi-asserted-by":"crossref","first-page":"31930","DOI":"10.1074\/jbc.274.45.31930","article-title":"Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit interleukin-12 transcription by regulating nuclear factor kappaB and Ets activation","volume":"274","author":"Delgado","year":"1999","journal-title":"J Biol Chem"},{"issue":"7","key":"2019111616104359100_B51","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1084\/jem.20021610","article-title":"Combined deficiency of p50 and cRel in CD4+ T cells reveals an essential requirement for nuclear factor kappaB in regulating mature T cell survival and in vivo function","volume":"197","author":"Zheng","year":"2003","journal-title":"J Exp Med"}],"container-title":["Blood Advances"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/ashpublications.org\/bloodadvances\/article-pdf\/2\/3\/210\/880130\/advances011254.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/ashpublications.org\/bloodadvances\/article-pdf\/2\/3\/210\/880130\/advances011254.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,30]],"date-time":"2025-06-30T10:59:19Z","timestamp":1751281159000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/bloodadvances\/article\/2\/3\/210\/15774\/Improving-Tcell-expansion-and-function-for"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,1,31]]},"references-count":51,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2018,2,13]]}},"URL":"https:\/\/doi.org\/10.1182\/bloodadvances.2017011254","relation":{},"ISSN":["2473-9529","2473-9537"],"issn-type":[{"value":"2473-9529","type":"print"},{"value":"2473-9537","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,1,31]]}}}