{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T10:47:35Z","timestamp":1788432455705,"version":"build-2803163510"},"reference-count":61,"publisher":"National Academy of Sciences","issue":"10","license":[{"start":{"date-parts":[[2024,2,26]],"date-time":"2024-02-26T00:00:00Z","timestamp":1708905600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006955","name":"HHS | NIH | Office of Extramural Research","doi-asserted-by":"publisher","award":["T32GM008076"],"award-info":[{"award-number":["T32GM008076"]}],"id":[{"id":"10.13039\/100006955","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006955","name":"HHS | NIH | Office of Extramural Research","doi-asserted-by":"publisher","award":["5T32CA009140"],"award-info":[{"award-number":["5T32CA009140"]}],"id":[{"id":"10.13039\/100006955","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"HHS | NIH | National Cancer Institute","doi-asserted-by":"publisher","award":["CA278837"],"award-info":[{"award-number":["CA278837"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,3,5]]},"abstract":"<jats:p>\n                    Chimeric antigen receptor (CAR) T cell dysfunction is a major barrier to achieving lasting remission in hematologic cancers, especially in chronic lymphocytic leukemia (CLL). We have shown previously that \u0394133p53\u03b1, an endogenous isoform of the human TP53 gene, decreases in expression with age in human T cells, and that reconstitution of \u0394133p53\u03b1 in poorly functional T cells can rescue proliferation [A. M. Mondal\n                    <jats:italic>et al.<\/jats:italic>\n                    ,\n                    <jats:italic>J. Clin. Invest.<\/jats:italic>\n                    <jats:bold>123<\/jats:bold>\n                    , 5247\u20135257 (2013)]. Although \u0394133p53\u03b1 lacks a transactivation domain, it can form heterooligomers with full-length p53 and modulate the p53-mediated stress response [I. Horikawa\n                    <jats:italic>et al.<\/jats:italic>\n                    ,\n                    <jats:italic>Cell Death Differ.<\/jats:italic>\n                    <jats:bold>24<\/jats:bold>\n                    , 1017\u20131028 (2017)]. Here, we show that constitutive expression of \u0394133p53\u03b1 potentiates the anti-tumor activity of CD19-directed CAR T cells and limits dysfunction under conditions of high tumor burden and metabolic stress. We demonstrate that \u0394133p53\u03b1-expressing CAR T cells exhibit a robust metabolic phenotype, maintaining the ability to execute effector functions and continue proliferating under nutrient-limiting conditions, in part due to upregulation of critical biosynthetic processes and improved mitochondrial function. Importantly, we show that our strategy to constitutively express \u0394133p53\u03b1 improves the anti-tumor efficacy of CAR T cells generated from CLL patients that previously failed CAR T cell therapy. More broadly, our results point to the potential role of the p53-mediated stress response in limiting the prolonged antitumor functions required for complete tumor clearance in patients with high disease burden, suggesting that modulation of the p53 signaling network with \u0394133p53\u03b1 may represent a translationally viable strategy for improving CAR T cell therapy.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2317735121","type":"journal-article","created":{"date-parts":[[2024,2,26]],"date-time":"2024-02-26T15:00:36Z","timestamp":1708959636000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":23,"title":["Enhancing chimeric antigen receptor T cell therapy by modulating the p53 signaling network with \u0394133p53\u03b1"],"prefix":"10.1073","volume":"121","author":[{"given":"Christopher","family":"Roselle","sequence":"first","affiliation":[{"name":"Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104"},{"name":"Pharmacology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Izumi","family":"Horikawa","sequence":"additional","affiliation":[{"name":"Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linhui","family":"Chen","sequence":"additional","affiliation":[{"name":"Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andre R.","family":"Kelly","sequence":"additional","affiliation":[{"name":"Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donna","family":"Gonzales","sequence":"additional","affiliation":[{"name":"Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tong","family":"Da","sequence":"additional","affiliation":[{"name":"Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nils","family":"Wellhausen","sequence":"additional","affiliation":[{"name":"Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104"},{"name":"Pharmacology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philipp C.","family":"Rommel","sequence":"additional","affiliation":[{"name":"Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104"},{"name":"Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Baker","sequence":"additional","affiliation":[{"name":"Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104"},{"name":"Pharmacology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104"},{"name":"Cardiovascular Institute, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan","family":"Suhoski","sequence":"additional","affiliation":[{"name":"Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Scholler","sequence":"additional","affiliation":[{"name":"Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roddy S.","family":"O\u2019Connor","sequence":"additional","affiliation":[{"name":"Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Regina M.","family":"Young","sequence":"additional","affiliation":[{"name":"Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104"},{"name":"Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Curtis C.","family":"Harris","sequence":"additional","affiliation":[{"name":"Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0241-3557","authenticated-orcid":false,"given":"Carl H.","family":"June","sequence":"additional","affiliation":[{"name":"Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104"},{"name":"Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2024,2,26]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3002842"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1407222"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-04390-6"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aac5415"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2022007423"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.780442"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0010-1"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tmrv.2019.01.005"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.927153"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2018885863"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1053\/j.seminhematol.2023.01.002"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-022-01765-8"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-med-062315-120245"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.3390\/biology12020287"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a026039"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a026328"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.15252\/embr.202153085"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.08.028"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm4007"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1339905"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1928"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a000927"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2017.48"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1177\/1947601911408893"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2010.91"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbcan.2023.188882"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2016.37"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1080\/15384101.2017.1345228"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-018-0767-7"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-017-0101-3"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI70355"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/dxaa006"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-020-0262-1"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-24676-6"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.05.016"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.07.009"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-022-02439-6"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2016.502"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12113422"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2015.22"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gku501"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2005.03.027"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M001020200"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80416-X"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2020.07.018"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-01-552174"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1007\/s13238-019-0643-y"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aar6711"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-021-00574-3"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-019-0297-y"},{"key":"e_1_3_4_51_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-020-0873-2"},{"key":"e_1_3_4_52_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-020-00834-9"},{"key":"e_1_3_4_53_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-042617-053019"},{"key":"e_1_3_4_54_2","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2020-001846"},{"key":"e_1_3_4_55_2","doi-asserted-by":"publisher","DOI":"10.15252\/msb.202110588"},{"key":"e_1_3_4_56_2","first-page":"6304","article-title":"Participation of p53 protein in the cellular response to DNA damage","volume":"51","author":"Kastan M. B.","year":"1991","unstructured":"M. B. Kastan, O. Onyekwere, D. Sidransky, B. Vogelstein, R. W. Craig, Participation of p53 protein in the cellular response to DNA damage. Cancer Res. 51, 6304\u20136311 (1991).","journal-title":"Cancer Res."},{"key":"e_1_3_4_57_2","doi-asserted-by":"publisher","DOI":"10.1038\/387299a0"},{"key":"e_1_3_4_58_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1203015"},{"key":"e_1_3_4_59_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.05.014"},{"key":"e_1_3_4_60_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0171257"},{"key":"e_1_3_4_61_2","doi-asserted-by":"crossref","unstructured":"C. Roselle L. Chen R. M. Young C. H. June Enhancing chimeric antigen receptor T cell therapy by modulating the p53 signaling network with \u0394133p53\u03b1. Gene Expression Omnibus (GEO). https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE248382. Deposited 21 November 2023.","DOI":"10.1073\/pnas.2317735121"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2317735121","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,12]],"date-time":"2024-11-12T17:42:36Z","timestamp":1731433356000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2317735121"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,26]]},"references-count":61,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2024,3,5]]}},"alternative-id":["10.1073\/pnas.2317735121"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2317735121","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,26]]},"assertion":[{"value":"2023-10-12","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-12-29","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-02-26","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2317735121"}}