{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T23:42:35Z","timestamp":1792798955920,"version":"4.5.0"},"reference-count":27,"publisher":"BMJ","issue":"7","license":[{"start":{"date-parts":[[2023,7,31]],"date-time":"2023-07-31T00:00:00Z","timestamp":1690761600000},"content-version":"unspecified","delay-in-days":30,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012232","name":"National Key Clinical Specialty Discipline Construction Program of China","doi-asserted-by":"publisher","award":["2021-76"],"award-info":[{"award-number":["2021-76"]}],"id":[{"id":"10.13039\/501100012232","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003347","name":"Fudan University","doi-asserted-by":"publisher","award":["JIH1322069"],"award-info":[{"award-number":["JIH1322069"]}],"id":[{"id":"10.13039\/501100003347","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Fujian Provincial Clinical Research Center for Hematological Malignancies","award":["2020Y2006"],"award-info":[{"award-number":["2020Y2006"]}]},{"name":"Fujian Provincial Department of Finance","award":["2021-917"],"award-info":[{"award-number":["2021-917"]}],"id":[{"id":"https:\/\/ror.org\/05rjrj969","id-type":"ROR","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82000142"],"award-info":[{"award-number":["82000142"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["U2005204"],"award-info":[{"award-number":["U2005204"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013795","name":"Fujian Medical University","doi-asserted-by":"publisher","award":["2019QH1060"],"award-info":[{"award-number":["2019QH1060"]}],"id":[{"id":"10.13039\/501100013795","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013795","name":"Fujian Medical University","doi-asserted-by":"publisher","award":["2019QH2012"],"award-info":[{"award-number":["2019QH2012"]}],"id":[{"id":"10.13039\/501100013795","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2023,6,28]]},"published-print":{"date-parts":[[2023,7]]},"abstract":"<jats:p>\n                    The treatment of B cell malignancies has dramatically changed with the introduction of immunotherapy, especially chimeric antigen receptor T (CAR-T) cell therapy. However, only limited efficacy is observed in acute myeloid leukaemia (AML). In the study, We detected CD123 and CLL-1 expression on leukaemia cells from Relapsed\/Refractory AML (R\/R AML) patients. Then, we constructed anti-CD123 CAR and CLL-1 CAR with different co-stimulation domains (CD28 or 4-1BB) and detected their anti-AML effects. To increase the efficacy of CAR-T cell therapy, we tested different strategies, including application of combined checkpoint inhibitors and histone deacetylase inhibitors (HDACi)\n                    <jats:italic>in vivo<\/jats:italic>\n                    and\n                    <jats:italic>in vitro<\/jats:italic>\n                    . We found CD123 and CLL-1 were highly expressed on AML cells. The proportions of T cell subsets and NK cells involved in anti-tumour or anti-inflammation processes in AML patients significantly decreased when compared with healthy donors. Both CD123 CAR and CLL-1 CAR displayed specific anti-AML effects\n                    <jats:italic>in vitro<\/jats:italic>\n                    . To improve the lysis effects of CAR-T cells, we combined CAR-T cell therapy with different agents. PD-1\/PD-L1 antibodies only slightly improved the potency of CAR-T cell therapy (CD123 CAR-T 60.92% \u00b1 2.9087% vs. 65.43% \u00b1 2.1893%, 60.92% \u00b1 2.9087% vs. 67.43% \u00b1 3.4973%; 37.37% \u00b1 3.908% vs. 41.89% \u00b1 5.1568%, 37.37% \u00b1 3.908% vs. 42.84% \u00b1 4.2635%). However, one HDACi (valproic acid [VPA]) significantly improved CAR-T cell potency against AML cells (CLL-1 CAR-T 34.97% \u00b1 0.3051% vs. 88.167% \u00b1 1.5327%, p &lt; 0.0001; CD123 CAR-T 26.87% \u00b1 2.7010% vs. 82.56% \u00b1 3.086%, p &lt; 0.0001 in MV411; CLL-1 CAR-T 78.77% \u00b1 1.2061% vs. 93.743% \u00b1 1.2333%, p &lt; 0.0001; CD123 CAR-T 64.10% \u00b1 1.5130% vs. 94.427% \u00b1 0.142%, p = 0.0001 in THP-1). Combination therapy prolonged the overall survival of mice when compared with single CD123 CAR-T cell therapy (median survival: 180 days vs. unfollowed). A possible mechanism is that activated CD8+T cells upregulate natural-killer group 2 member D (NKG2D), and VPA upregulates NKG2D ligand expression in AML cells, contributing to NKG2D-mediated cytotoxicity of CAR-T cells against tumour cells. In conclusion, CD123 and CLL-1 are promising targets for AML CAR-T cell therapy. A combination of VPA pre-treatment and CAR-T against AML exhibits synergic effects.\n                  <\/jats:p>","DOI":"10.1136\/jitc-2023-006857","type":"journal-article","created":{"date-parts":[[2023,7,31]],"date-time":"2023-07-31T13:50:16Z","timestamp":1690811416000},"page":"e006857","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":33,"title":["Valproic acid increases CAR T cell cytotoxicity against acute myeloid leukemia"],"prefix":"10.1136","volume":"11","author":[{"given":"Jingjing","family":"Wen","sequence":"first","affiliation":[{"name":"Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fujian Institute of Hematology, Fuzhou, China"},{"name":"Department of Lymphoma, Fujian Cancer Hospital, Fuzhou, People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanxin","family":"Chen","sequence":"additional","affiliation":[{"name":"Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fujian Institute of Hematology, Fuzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiajie","family":"Yang","sequence":"additional","affiliation":[{"name":"Fujian Provincial Key Laboratory of Hematology, Fujian Medical University Union Hospital, Fujian Institute of Hematology, Fuzhou, China"},{"name":"Institute of Precision Medicine, Fujian Medical University, Fuzhou, People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunye","family":"Dai","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Fudan University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shenjie","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Internal medicine, The First Affiliated Hospital of Xiamen University, Xiamen, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenting","family":"Zhong","sequence":"additional","affiliation":[{"name":"Department of Research and Development, ST Phi Therapeutics Co., Ltd, Hangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lilin","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Research and Development, ST Phi Therapeutics Co., Ltd, Hangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengguanng","family":"He","sequence":"additional","affiliation":[{"name":"Department of Research and Development, ST Phi Therapeutics Co., Ltd, Hangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenmin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Precision Medicine, Fujian Medical University, Fuzhou, People's Republic of China"},{"name":"Pathological Diagnosis Center & Oncology Institution, Fujian Medical 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