{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T12:05:36Z","timestamp":1792670736219,"version":"4.5.0"},"reference-count":39,"publisher":"American Society of Hematology","issue":"18","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2024,10,31]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>DNA methyltransferase inhibitor decitabine plus anti\u2013programmed cell death 1 (DP) therapy was effective in relapsed\/refractory classic Hodgkin lymphoma (cHL). However, a subset of patients experienced primary resistance or relapse\/progression after DP therapy. In this study, we evaluated the efficacy and safety of a triplet regimen consisting of the histone deacetylase inhibitor chidamide, decitabine, and anti\u2013PD-1 camrelizumab (CDP) in 52 patients who previously received DP therapy. CDP treatment was well tolerated and resulted in an objective response rate of 94% (95% confidence interval [CI], 84-99), with 50% (95% CI, 36-64) of patients achieving complete response (CR). Notably, all patients who were recalcitrant to previous DP treatment exhibited therapeutic responses after CDP therapy, although their CR rate was lower than patients responsive to prior DP. Overall, the median progression-free survival was 29.4 months. Through single-cell RNA sequencing of pretreatment and on-treatment cHL tumor biopsy samples, we observed the heterogeneity of rare malignant Hodgkin Reed\/Sternberg (HRS)\u2013like cells. The classical CD30+ HRS-like cells interacted with abundant immunosuppressive IL21+CD4+ T helper cells, forming a positive feedback loop that supported their survival. While the CD30\u2013 HRS-like cell population showed potential resistance to anti\u2013PD-1 immunotherapy. CDP treatment promoted the activation of diverse tumor-reactive CD8+ T cells and suppressed the proliferation of IL21+CD4+ T cells by inhibiting STAT1\/3 signaling, thereby alleviating their immunosuppressive effects. These findings provide insights into the cHL microenvironment that contributes to anti\u2013PD-1 resistance and highlight the therapeutic effectiveness of dual epi-immunotherapy in overcoming immunotherapy resistance. This trial was registered at www.clinicaltrials.gov as #NCT04233294.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1182\/blood.2024024487","type":"journal-article","created":{"date-parts":[[2024,8,2]],"date-time":"2024-08-02T13:55:59Z","timestamp":1722606959000},"page":"1936-1950","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":29,"title":["Epigenetic agents plus anti-PD-1 reprogram the tumor microenvironment and restore antitumor efficacy in Hodgkin lymphoma"],"prefix":"10.1182","volume":"144","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5080-6553","authenticated-orcid":false,"given":"Jing","family":"Nie","sequence":"first","affiliation":[{"name":"1Department of Biotherapeutics, The First Medical Center, Chinese People's Liberation Army General Hospital, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunmeng","family":"Wang","sequence":"additional","affiliation":[{"name":"1Department of Biotherapeutics, The First Medical Center, Chinese People's Liberation Army General Hospital, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9795-3198","authenticated-orcid":false,"given":"Liangtao","family":"Zheng","sequence":"additional","affiliation":[{"name":"2Analytical Biosciences Limited, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Liu","sequence":"additional","affiliation":[{"name":"1Department of Biotherapeutics, The First Medical Center, Chinese People's Liberation Army General Hospital, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-5331-9058","authenticated-orcid":false,"given":"Chengcheng","family":"Wang","sequence":"additional","affiliation":[{"name":"2Analytical Biosciences Limited, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yixin","family":"Chang","sequence":"additional","affiliation":[{"name":"1Department of Biotherapeutics, The First Medical Center, Chinese People's Liberation Army General Hospital, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yudi","family":"Hu","sequence":"additional","affiliation":[{"name":"2Analytical Biosciences Limited, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing","family":"Guo","sequence":"additional","affiliation":[{"name":"1Department of Biotherapeutics, The First Medical Center, Chinese People's Liberation Army General Hospital, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuting","family":"Pan","sequence":"additional","affiliation":[{"name":"1Department of Biotherapeutics, The First Medical Center, Chinese People's Liberation Army General Hospital, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingming","family":"Yang","sequence":"additional","affiliation":[{"name":"1Department of Biotherapeutics, The First Medical Center, Chinese People's Liberation Army General Hospital, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueda","family":"Hu","sequence":"additional","affiliation":[{"name":"2Analytical Biosciences Limited, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3207-3899","authenticated-orcid":false,"given":"Weidong","family":"Han","sequence":"additional","affiliation":[{"name":"1Department of Biotherapeutics, The First Medical Center, Chinese People's Liberation Army General Hospital, Beijing, China"},{"name":"3Changping Laboratory, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","reference":[{"issue":"9","key":"2024110813454209400_bib1","doi-asserted-by":"crossref","first-page":"1283","DOI":"10.1016\/S1470-2045(16)30167-X","article-title":"Nivolumab for classical Hodgkin's lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a\u00a0multicentre, multicohort, single-arm phase\u00a02 trial","volume":"17","author":"Younes","year":"2016","journal-title":"Lancet Oncol"},{"issue":"19","key":"2024110813454209400_bib2","doi-asserted-by":"crossref","first-page":"2125","DOI":"10.1200\/JCO.2016.72.1316","article-title":"Phase II study of the efficacy and safety of pembrolizumab for relapsed\/refractory classic Hodgkin lymphoma","volume":"35","author":"Chen","year":"2017","journal-title":"J\u00a0Clin Oncol"},{"issue":"14","key":"2024110813454209400_bib3","doi-asserted-by":"crossref","first-page":"1428","DOI":"10.1200\/JCO.2017.76.0793","article-title":"Nivolumab for relapsed\/refractory classic Hodgkin lymphoma after failure of autologous hematopoietic cell transplantation: extended follow-up of the multicohort single-arm phase II CheckMate 205 Trial","volume":"36","author":"Armand","year":"2018","journal-title":"J\u00a0Clin Oncol"},{"issue":"4","key":"2024110813454209400_bib4","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1056\/NEJMoa1411087","article-title":"PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma","volume":"372","author":"Ansell","year":"2015","journal-title":"N\u00a0Engl J Med"},{"issue":"17","key":"2024110813454209400_bib5","doi-asserted-by":"crossref","first-page":"1479","DOI":"10.1200\/JCO.18.02151","article-title":"Addition of low-dose decitabine to anti-PD-1 antibody camrelizumab in relapsed\/refractory classical Hodgkin lymphoma","volume":"37","author":"Nie","year":"2019","journal-title":"J\u00a0Clin Oncol"},{"issue":"23","key":"2024110813454209400_bib6","doi-asserted-by":"crossref","first-page":"2690","DOI":"10.1200\/JCO.2016.66.4482","article-title":"PD-L1 and PD-L2 genetic alterations define classical Hodgkin lymphoma and predict outcome","volume":"34","author":"Roemer","year":"2016","journal-title":"J\u00a0Clin Oncol"},{"issue":"3","key":"2024110813454209400_bib7","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1158\/2159-8290.CD-19-0680","article-title":"Single-cell transcriptome analysis reveals disease-defining T-cell subsets in the tumor microenvironment of classic Hodgkin lymphoma","volume":"10","author":"Aoki","year":"2020","journal-title":"Cancer Discov"},{"issue":"22","key":"2024110813454209400_bib8","doi-asserted-by":"crossref","first-page":"2420","DOI":"10.1182\/blood-2017-03-770719","article-title":"Topological analysis reveals a PD-L1-associated microenvironmental niche for Reed-Sternberg cells in Hodgkin lymphoma","volume":"130","author":"Carey","year":"2017","journal-title":"Blood"},{"issue":"7","key":"2024110813454209400_bib9","doi-asserted-by":"crossref","first-page":"e165673","DOI":"10.1172\/JCI165673","article-title":"Decitabine priming increases anti-PD-1 antitumor efficacy by promoting CD8+ progenitor exhausted T cell expansion in tumor models","volume":"133","author":"Li","year":"2023","journal-title":"J\u00a0Clin Invest"},{"issue":"8","key":"2024110813454209400_bib10","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1038\/s41571-019-0190-8","article-title":"Emerging epigenetic-modulating therapies in lymphoma","volume":"16","author":"Sermer","year":"2019","journal-title":"Nat Rev Clin Oncol"},{"issue":"4","key":"2024110813454209400_bib11","doi-asserted-by":"crossref","first-page":"e002347","DOI":"10.1136\/jitc-2021-002347","article-title":"Improved clinical outcome in a randomized phase II study of anti-PD-1 camrelizumab plus decitabine in relapsed\/refractory Hodgkin lymphoma","volume":"9","author":"Liu","year":"2021","journal-title":"J\u00a0Immunother Cancer"},{"issue":"6","key":"2024110813454209400_bib12","doi-asserted-by":"crossref","first-page":"e428","DOI":"10.1002\/mco2.428","article-title":"Long-term complete remission and peripheral biomarkers in Hodgkin lymphoma patients after decitabine-plus-camrelizumab epi-immunotherapy and treatment cessation","volume":"4","author":"Wang","year":"2023","journal-title":"MedComm (2020)"},{"issue":"10","key":"2024110813454209400_bib13","doi-asserted-by":"crossref","first-page":"2782","DOI":"10.1158\/1078-0432.CCR-21-0133","article-title":"Efficacy of decitabine plus anti-PD-1 camrelizumab in patients with Hodgkin lymphoma who progressed or relapsed after PD-1 blockade monotherapy","volume":"27","author":"Wang","year":"2021","journal-title":"Clin Cancer Res"},{"issue":"18","key":"2024110813454209400_bib14","doi-asserted-by":"crossref","first-page":"2197","DOI":"10.1200\/JCO.2011.38.1350","article-title":"Panobinostat in patients with relapsed\/refractory Hodgkin's lymphoma after autologous stem-cell transplantation: results of a phase II study","volume":"30","author":"Younes","year":"2012","journal-title":"J\u00a0Clin Oncol"},{"issue":"16","key":"2024110813454209400_bib15","doi-asserted-by":"crossref","first-page":"1359","DOI":"10.1182\/blood.2023020485","article-title":"Pembrolizumab plus vorinostat induces responses in patients with Hodgkin lymphoma refractory to prior PD-1 blockade","volume":"142","author":"Mei","year":"2023","journal-title":"Blood"},{"issue":"17","key":"2024110813454209400_bib16","doi-asserted-by":"crossref","first-page":"3530","DOI":"10.1182\/blood-2012-06-439570","article-title":"Gene expression profiling of microdissected Hodgkin Reed-Sternberg cells correlates with treatment outcome in classical Hodgkin lymphoma","volume":"120","author":"Steidl","year":"2012","journal-title":"Blood"},{"issue":"5878","key":"2024110813454209400_bib17","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1038\/299065a0","article-title":"Production of a monoclonal antibody specific for Hodgkin and Sternberg-Reed cells of Hodgkin's disease and a subset of normal lymphoid cells","volume":"299","author":"Schwab","year":"1982","journal-title":"Nature"},{"issue":"1","key":"2024110813454209400_bib18","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1038\/s41572-020-0189-6","article-title":"Hodgkin lymphoma","volume":"6","author":"Connors","year":"2020","journal-title":"Nat Rev Dis Primers"},{"issue":"12","key":"2024110813454209400_bib19","doi-asserted-by":"crossref","first-page":"1408","DOI":"10.1038\/s41587-020-0591-3","article-title":"Generalizing RNA velocity to transient cell states through dynamical modeling","volume":"38","author":"Bergen","year":"2020","journal-title":"Nat Biotechnol"},{"issue":"1","key":"2024110813454209400_bib20","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1186\/s13287-022-02803-5","article-title":"StemSC: a cross-dataset human stemness index for single-cell samples","volume":"13","author":"Zheng","year":"2022","journal-title":"Stem Cell Res Ther"},{"issue":"1","key":"2024110813454209400_bib21","doi-asserted-by":"crossref","first-page":"4415","DOI":"10.1038\/s41467-019-12446-5","article-title":"CXCR5(+)PD-1(+) follicular helper CD8 T cells control B cell tolerance","volume":"10","author":"Chen","year":"2019","journal-title":"Nat Commun"},{"issue":"4","key":"2024110813454209400_bib22","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1038\/s41568-019-0235-4","article-title":"CD8(+) T cell states in human cancer: insights from single-cell analysis","volume":"20","author":"van der Leun","year":"2020","journal-title":"Nat Rev Cancer"},{"issue":"7735","key":"2024110813454209400_bib23","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1038\/s41586-018-0694-x","article-title":"Lineage tracking reveals dynamic relationships of T\u00a0cells in colorectal cancer","volume":"564","author":"Zhang","year":"2018","journal-title":"Nature"},{"issue":"41","key":"2024110813454209400_bib24","doi-asserted-by":"crossref","first-page":"e2105822118","DOI":"10.1073\/pnas.2105822118","article-title":"Single-cell profiling reveals the importance of CXCL13\/CXCR5 axis biology in lymphocyte-rich classic Hodgkin lymphoma","volume":"118","author":"Aoki","year":"2021","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"7919","key":"2024110813454209400_bib25","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1038\/s41586-022-04918-4","article-title":"Single-cell roadmap of human gonadal development","volume":"607","author":"Garcia-Alonso","year":"2022","journal-title":"Nature"},{"issue":"2","key":"2024110813454209400_bib26","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1038\/s41592-019-0667-5","article-title":"NicheNet: modeling intercellular communication by linking ligands to target genes","volume":"17","author":"Browaeys","year":"2020","journal-title":"Nat Methods"},{"issue":"4","key":"2024110813454209400_bib27","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1038\/s41375-021-01204-6","article-title":"Molecular biology of Hodgkin lymphoma","volume":"35","author":"Weniger","year":"2021","journal-title":"Leukemia"},{"issue":"13","key":"2024110813454209400_bib28","doi-asserted-by":"crossref","first-page":"1489","DOI":"10.1182\/blood-2018-08-871293","article-title":"Autocrine LTA signaling drives NF-kappa B and JAK-STAT activity and myeloid gene expression in Hodgkin lymphoma","volume":"133","author":"von Hoff","year":"2019","journal-title":"Blood"},{"issue":"8","key":"2024110813454209400_bib29","doi-asserted-by":"crossref","first-page":"3339","DOI":"10.1182\/blood-2008-01-134783","article-title":"Aberrant expression of the Th2 cytokine IL-21 in Hodgkin lymphoma cells regulates STAT3 signaling and attracts T-reg cells via regulation of MIP-3 alpha","volume":"112","author":"Lamprecht","year":"2008","journal-title":"Blood"},{"issue":"10","key":"2024110813454209400_bib30","doi-asserted-by":"crossref","first-page":"2251","DOI":"10.1084\/jem.20080809","article-title":"Origin and pathogenesis of nodular lymphocyte-predominant Hodgkin lymphoma as revealed by global gene expression analysis","volume":"205","author":"Brune","year":"2008","journal-title":"J\u00a0Exp Med"},{"issue":"3","key":"2024110813454209400_bib31","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1038\/s41577-019-0224-6","article-title":"TIM3 comes of age as an inhibitory receptor","volume":"20","author":"Wolf","year":"2020","journal-title":"Nat Rev Immunol"},{"issue":"4","key":"2024110813454209400_bib32","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1007\/s00280-011-1766-x","article-title":"Chidamide (CS055\/HBI-8000): a new histone deacetylase inhibitor of the benzamide class with antitumor activity and the ability to enhance immune cell-mediated tumor cell cytotoxicity","volume":"69","author":"Ning","year":"2012","journal-title":"Cancer Chemother Pharmacol"},{"issue":"12","key":"2024110813454209400_bib33","doi-asserted-by":"crossref","first-page":"1789","DOI":"10.1039\/C4MD00350K","article-title":"Discovery of an orally active subtype-selective HDAC inhibitor, chidamide, as an epigenetic modulator for cancer treatment","volume":"5","author":"Pan","year":"2014","journal-title":"Medchemcomm"},{"issue":"11","key":"2024110813454209400_bib34","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1038\/nmeth.4463","article-title":"SCENIC: single-cell regulatory network inference and clustering","volume":"14","author":"Aibar","year":"2017","journal-title":"Nat Methods"},{"issue":"1","key":"2024110813454209400_bib35","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1111\/his.14910","article-title":"CD30 expression is frequently decreased in relapsed classic Hodgkin lymphoma after anti-CD30 CAR T-cell therapy","volume":"83","author":"Marques-Piubelli","year":"2023","journal-title":"Histopathology"},{"issue":"6","key":"2024110813454209400_bib36","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1182\/blood.2021013881","article-title":"Relapsed classic Hodgkin\u00a0lymphoma with decreased CD30 expression after brentuximab and anti-CD30 CAR-T therapies","volume":"139","author":"Kim","year":"2022","journal-title":"Blood"},{"issue":"12","key":"2024110813454209400_bib37","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1111\/cup.12797","article-title":"Loss of CD30 expression after treatment with brentuximab vedotin in a patient with anaplastic large cell lymphoma: a novel finding","volume":"43","author":"Al-Rohil","year":"2016","journal-title":"J\u00a0Cutan Pathol"},{"issue":"11","key":"2024110813454209400_bib38","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1111\/cup.13545","article-title":"Variable loss of CD30 expression by immunohistochemistry in recurrent cutaneous CD30+ lymphoid neoplasms treated with brentuximab vedotin","volume":"46","author":"Goyal","year":"2019","journal-title":"J\u00a0Cutan Pathol"},{"issue":"6","key":"2024110813454209400_bib39","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1038\/ni.2019","article-title":"Germinal center B and follicular helper T cells: siblings, cousins or just good friends?","volume":"12","author":"Nutt","year":"2011","journal-title":"Nat Immunol"}],"container-title":["Blood"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/144\/18\/1936\/2312732\/blood_bld-2024-024487-main.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/144\/18\/1936\/2312732\/blood_bld-2024-024487-main.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,8]],"date-time":"2024-11-08T08:45:57Z","timestamp":1731055557000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/blood\/article\/144\/18\/1936\/517268\/Epigenetic-agents-plus-anti-PD-1-reprogram-the"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,31]]},"references-count":39,"journal-issue":{"issue":"18","published-print":{"date-parts":[[2024,10,31]]}},"URL":"https:\/\/doi.org\/10.1182\/blood.2024024487","relation":{},"ISSN":["0006-4971","1528-0020"],"issn-type":[{"value":"0006-4971","type":"print"},{"value":"1528-0020","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,31]]}}}