{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T13:14:32Z","timestamp":1783948472401,"version":"3.55.0"},"reference-count":42,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T00:00:00Z","timestamp":1761523200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T00:00:00Z","timestamp":1761523200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Leukemia"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Immunotherapeutic approaches have become increasingly important in cancer therapy, including for patients with acute myeloid leukemia (AML). Despite being shown to be effective in the context of stem cell transplants for almost 50 years, further improvements are required to prevent relapse and its associated morbidity. The therapeutic use of immune checkpoint inhibition in AML is still under debate. We have shown some positive effects of it on cancer control ex vivo. We found that anti-programmed death-1 (PD-1) antibodies in combination with azacitidine (AZA) had the most pronounced effect on T-cell activation and control of leukemic progenitor\/stem cell growth. We identified which leukemia-associated antigen (LAA) stimulated the largest IFN\u03b3 immune response by T cells from AML patients with and without the nucleophosmin 1 (NPM1) mutation and which immunotherapeutic strategy, either alone or in combination with the immune checkpoint anti-PD-1, could enhance immune responses against leukemic cells. Anti-PD-1 with AZA had a particularly strong effect with a mean colony reduction of 56%. Taken together, combinations of immunotherapeutic approaches increase antigen-specific immune responses against leukemic cells but also leukemic progenitor\/stem cells. The combination of LAA-peptides with anti-PD-1 antibody and one further immunotherapeutic could be an interesting option for further clinical studies.<\/jats:p>","DOI":"10.1038\/s41375-025-02764-7","type":"journal-article","created":{"date-parts":[[2025,10,27]],"date-time":"2025-10-27T10:07:41Z","timestamp":1761559661000},"page":"130-137","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Different immunotherapeutic combinations enhance specific T cell immune responses against leukemic cells, as well as leukemic progenitor cells, in acute myeloid leukemia"],"prefix":"10.1038","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1256-173X","authenticated-orcid":false,"given":"Jochen","family":"Greiner","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick J.","family":"Schuler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hubert","family":"Schrezenmeier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna","family":"Weiss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christiane","family":"Bulach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marlies","family":"Goetz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0639-4541","authenticated-orcid":false,"given":"Barbara-ann","family":"Guinn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,27]]},"reference":[{"key":"2764_CR1","doi-asserted-by":"publisher","first-page":"424","DOI":"10.1182\/blood-2016-08-733196","volume":"129","author":"H Dohner","year":"2017","unstructured":"Dohner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Buchner T, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129:424\u201347.","journal-title":"Blood"},{"key":"2764_CR2","doi-asserted-by":"publisher","first-page":"1186","DOI":"10.1002\/cncr.33477","volume":"127","author":"HM Kantarjian","year":"2021","unstructured":"Kantarjian HM, Kadia TM, DiNardo CD, Welch MA, Ravandi F. Acute myeloid leukemia: Treatment and research outlook for 2021 and the MD Anderson approach. Cancer. 2021;127:1186\u2013207.","journal-title":"Cancer"},{"key":"2764_CR3","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1002\/cncr.33933","volume":"128","author":"HM Kantarjian","year":"2022","unstructured":"Kantarjian HM, Jain N, Garcia-Manero G, Welch MA, Ravandi F, Wierda WG, et al. The cure of leukemia through the optimist\u2019s prism. Cancer. 2022;128:240\u201359.","journal-title":"Cancer"},{"key":"2764_CR4","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1038\/s41375-021-01350-x","volume":"36","author":"S Tettamanti","year":"2022","unstructured":"Tettamanti S, Pievani A, Biondi A, Dotti G, Serafini M. Catch me if you can: how AML and its niche escape immunotherapy. Leukemia. 2022;36:13\u201322.","journal-title":"Leukemia"},{"key":"2764_CR5","doi-asserted-by":"crossref","unstructured":"Forghieri F, Riva G, Lagreca I, Barozzi P, Bettelli F, Paolini A, et al. Neoantigen-Specific T-Cell Immune Responses: The Paradigm of NPM1-Mutated Acute Myeloid Leukemia. Int J Mol Sci. 2021;22.","DOI":"10.3390\/ijms22179159"},{"key":"2764_CR6","doi-asserted-by":"publisher","first-page":"e448","DOI":"10.1016\/S2352-3026(24)00098-X","volume":"11","author":"S Pagliuca","year":"2024","unstructured":"Pagliuca S, Schmid C, Santoro N, Simonetta F, Battipaglia G, Guillaume T, et al. Donor lymphocyte infusion after allogeneic haematopoietic cell transplantation for haematological malignancies: basic considerations and best practice recommendations from the EBMT. Lancet Haematol. 2024;11:e448\u2013e58.","journal-title":"Lancet Haematol"},{"key":"2764_CR7","doi-asserted-by":"publisher","first-page":"330","DOI":"10.1007\/s12185-022-03416-7","volume":"116","author":"F Kreidieh","year":"2022","unstructured":"Kreidieh F, Abou Dalle I, Moukalled N, El-Cheikh J, Brissot E, Mohty M, et al. Relapse after allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia: an overview of prevention and treatment. Int J Hematol. 2022;116:330\u201340.","journal-title":"Int J Hematol"},{"key":"2764_CR8","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1111\/bjh.16310","volume":"188","author":"AJ Barrett","year":"2020","unstructured":"Barrett AJ. Acute myeloid leukaemia and the immune system: implications for immunotherapy. Br J Haematol. 2020;188:147\u201358.","journal-title":"Br J Haematol"},{"key":"2764_CR9","doi-asserted-by":"publisher","first-page":"n2026","DOI":"10.1136\/bmj.n2026","volume":"375","author":"LF Newell","year":"2021","unstructured":"Newell LF, Cook RJ. Advances in acute myeloid leukemia. BMJ. 2021;375:n2026.","journal-title":"BMJ"},{"key":"2764_CR10","doi-asserted-by":"publisher","first-page":"819","DOI":"10.1080\/17474086.2023.2268273","volume":"16","author":"DR Spillane","year":"2023","unstructured":"Spillane DR, Assouline S. Immunotherapy for myelodysplastic syndrome and acute myeloid leukemia: where do we stand?. Expert Rev Hematol. 2023;16:819\u201334.","journal-title":"Expert Rev Hematol"},{"key":"2764_CR11","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1016\/j.critrevonc.2017.05.010","volume":"116","author":"AC Schuh","year":"2017","unstructured":"Schuh AC, Dohner H, Pleyer L, Seymour JF, Fenaux P, Dombret H. Azacitidine in adult patients with acute myeloid leukemia. Crit Rev Oncol Hematol. 2017;116:159\u201377.","journal-title":"Crit Rev Oncol Hematol"},{"key":"2764_CR12","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1007\/s11912-024-01503-y","volume":"26","author":"M Wysota","year":"2024","unstructured":"Wysota M, Konopleva M, Mitchell S. Novel Therapeutic Targets in Acute Myeloid Leukemia (AML). Curr Oncol Rep. 2024;26:409\u201320.","journal-title":"Curr Oncol Rep"},{"key":"2764_CR13","doi-asserted-by":"publisher","first-page":"1790","DOI":"10.1002\/ajh.27434","volume":"99","author":"J Marvin-Peek","year":"2024","unstructured":"Marvin-Peek J, Gilbert JS, Pollyea DA, DiNardo CD. Frontline therapy of acute myeloid leukemia with lower intensity regimens: Where are we now and where can we go?. Am J Hematol. 2024;99:1790\u2013801.","journal-title":"Am J Hematol"},{"key":"2764_CR14","doi-asserted-by":"crossref","unstructured":"Abaza Y, Zeidan AM Immune Checkpoint Inhibition in Acute Myeloid Leukemia and Myelodysplastic Syndromes. Cells. 2022;11.","DOI":"10.3390\/cells11142249"},{"key":"2764_CR15","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2023.1288172","volume":"13","author":"A Tsumura","year":"2023","unstructured":"Tsumura A, Levis D, Tuscano JM. Checkpoint inhibition in hematologic malignancies. Front Oncol. 2023;13:1288172.","journal-title":"Front Oncol"},{"key":"2764_CR16","doi-asserted-by":"publisher","first-page":"342","DOI":"10.1038\/s41571-022-00607-3","volume":"19","author":"L Amini","year":"2022","unstructured":"Amini L, Silbert SK, Maude SL, Nastoupil LJ, Ramos CA, Brentjens RJ, et al. Preparing for CAR T cell therapy: patient selection, bridging therapies and lymphodepletion. Nat Rev Clin Oncol. 2022;19:342\u201355.","journal-title":"Nat Rev Clin Oncol"},{"key":"2764_CR17","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1016\/S0140-6736(23)00521-4","volume":"402","author":"N van de Donk","year":"2023","unstructured":"van de Donk N, Zweegman S. T-cell-engaging bispecific antibodies in cancer. Lancet. 2023;402:142\u201358.","journal-title":"Lancet"},{"key":"2764_CR18","doi-asserted-by":"crossref","unstructured":"Guinn BA, Schuler PJ, Schrezenmeier H, Hofmann S, Weiss J, Bulach C, et al. A Combination of the Immunotherapeutic Drug Anti-Programmed Death 1 with Lenalidomide Enhances Specific T Cell Immune Responses against Acute Myeloid Leukemia Cells. Int J Mol Sci. 2023;24.","DOI":"10.3390\/ijms24119285"},{"key":"2764_CR19","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1007\/s11864-023-01066-3","volume":"24","author":"RP Gale","year":"2023","unstructured":"Gale RP. Can Immune Therapy Cure Acute Myeloid Leukemia?. Curr Treat Options Oncol. 2023;24:381\u20136.","journal-title":"Curr Treat Options Oncol"},{"key":"2764_CR20","doi-asserted-by":"publisher","first-page":"866","DOI":"10.1111\/bjh.18326","volume":"198","author":"J Greiner","year":"2022","unstructured":"Greiner J, Goetz M, Schuler PJ, Bulach C, Hofmann S, Schrezenmeier H, et al. Enhanced stimulation of antigen-specific immune responses against nucleophosmin 1 mutated acute myeloid leukaemia by an anti-programmed death 1 antibody. Br J Haematol. 2022;198:866\u201374.","journal-title":"Br J Haematol"},{"key":"2764_CR21","doi-asserted-by":"crossref","unstructured":"Aureli A, Marziani B, Sconocchia T, Del Principe MI, Buzzatti E, Pasqualone G, et al. Immunotherapy as a Turning Point in the Treatment of Acute Myeloid Leukemia. Cancers (Basel). 2021;13.","DOI":"10.3390\/cancers13246246"},{"key":"2764_CR22","doi-asserted-by":"crossref","unstructured":"Tabata R, Chi S, Yuda J, Minami Y Emerging Immunotherapy for Acute Myeloid Leukemia. Int J Mol Sci. 2021;22.","DOI":"10.3390\/ijms22041944"},{"key":"2764_CR23","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.882531","volume":"12","author":"M Gomez-Llobell","year":"2022","unstructured":"Gomez-Llobell M, Peleteiro Raindo A, Climent Medina J, Gomez Centurion I, Mosquera Orgueira A. Immune Checkpoint Inhibitors in Acute Myeloid Leukemia: A Meta-Analysis. Front Oncol. 2022;12:882531.","journal-title":"Front Oncol"},{"key":"2764_CR24","doi-asserted-by":"publisher","first-page":"609","DOI":"10.3389\/fphar.2019.00609","volume":"10","author":"D Liao","year":"2019","unstructured":"Liao D, Wang M, Liao Y, Li J, Niu T. A Review of Efficacy and Safety of Checkpoint Inhibitor for the Treatment of Acute Myeloid Leukemia. Front Pharm. 2019;10:609.","journal-title":"Front Pharm"},{"key":"2764_CR25","doi-asserted-by":"publisher","first-page":"1094","DOI":"10.1038\/s41375-018-0070-8","volume":"32","author":"N Daver","year":"2018","unstructured":"Daver N, Boddu P, Garcia-Manero G, Yadav SS, Sharma P, Allison J, et al. Hypomethylating agents in combination with immune checkpoint inhibitors in acute myeloid leukemia and myelodysplastic syndromes. Leukemia. 2018;32:1094\u2013105.","journal-title":"Leukemia"},{"key":"2764_CR26","doi-asserted-by":"publisher","first-page":"2083","DOI":"10.1002\/ijc.29583","volume":"137","author":"V Schneider","year":"2015","unstructured":"Schneider V, Zhang L, Rojewski M, Fekete N, Schrezenmeier H, Erle A, et al. Leukemic progenitor cells are susceptible to targeting by stimulated cytotoxic T cells against immunogenic leukemia-associated antigens. Int J Cancer. 2015;137:2083\u201392.","journal-title":"Int J Cancer"},{"key":"2764_CR27","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1007\/s00262-020-02490-2","volume":"69","author":"J Greiner","year":"2020","unstructured":"Greiner J, Gotz M, Hofmann S, Schrezenmeier H, Wiesneth M, Bullinger L, et al. Specific T-cell immune responses against colony-forming cells including leukemic progenitor cells of AML patients were increased by immune checkpoint inhibition. Cancer Immunol Immunother. 2020;69:629\u201340.","journal-title":"Cancer Immunol Immunother"},{"key":"2764_CR28","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1007\/s00428-022-03430-4","volume":"482","author":"OK Weinberg","year":"2023","unstructured":"Weinberg OK, Porwit A, Orazi A, Hasserjian RP, Foucar K, Duncavage EJ, et al. The International Consensus Classification of acute myeloid leukemia. Virchows Arch. 2023;482:27\u201337.","journal-title":"Virchows Arch"},{"key":"2764_CR29","doi-asserted-by":"publisher","first-page":"1136","DOI":"10.1056\/NEJMra1406184","volume":"373","author":"H Dohner","year":"2015","unstructured":"Dohner H, Weisdorf DJ, Bloomfield CD. Acute Myeloid Leukemia. N Engl J Med. 2015;373:1136\u201352.","journal-title":"N Engl J Med"},{"key":"2764_CR30","doi-asserted-by":"crossref","unstructured":"Greiner J, Gotz M, Wais V Increasing Role of Targeted Immunotherapies in the Treatment of AML. Int J Mol Sci. 2022;23.","DOI":"10.3390\/ijms23063304"},{"key":"2764_CR31","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1182\/blood.2023022481","volume":"143","author":"F Thol","year":"2024","unstructured":"Thol F, Dohner H, Ganser A. How I treat refractory and relapsed acute myeloid leukemia. Blood. 2024;143:11\u201320.","journal-title":"Blood"},{"key":"2764_CR32","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1200\/JCO.21.02229","volume":"40","author":"JD Wolchok","year":"2022","unstructured":"Wolchok JD, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, et al. Long-Term Outcomes With Nivolumab Plus Ipilimumab or Nivolumab Alone Versus Ipilimumab in Patients With Advanced Melanoma. J Clin Oncol. 2022;40:127\u201337.","journal-title":"J Clin Oncol"},{"key":"2764_CR33","doi-asserted-by":"publisher","DOI":"10.1038\/s41408-021-00453-z","volume":"11","author":"PK Reville","year":"2021","unstructured":"Reville PK, Kantarjian HM, Ravandi F, Jabbour E, DiNardo CD, Daver N, et al. Nivolumab maintenance in high-risk acute myeloid leukemia patients: a single-arm, open-label, phase II study. Blood Cancer J. 2021;11:60.","journal-title":"Blood Cancer J"},{"key":"2764_CR34","doi-asserted-by":"publisher","first-page":"1162","DOI":"10.3389\/fonc.2019.01162","volume":"9","author":"LM Mendez","year":"2019","unstructured":"Mendez LM, Posey RR, Pandolfi PP. The Interplay Between the Genetic and Immune Landscapes of AML: Mechanisms and Implications for Risk Stratification and Therapy. Front Oncol. 2019;9:1162.","journal-title":"Front Oncol"},{"key":"2764_CR35","doi-asserted-by":"publisher","DOI":"10.1038\/s41408-021-00514-3","volume":"11","author":"M Yilmaz","year":"2021","unstructured":"Yilmaz M, Kantarjian H, Ravandi F. Acute promyelocytic leukemia current treatment algorithms. Blood Cancer J. 2021;11:123.","journal-title":"Blood Cancer J"},{"key":"2764_CR36","doi-asserted-by":"publisher","first-page":"3369","DOI":"10.1182\/blood-2015-04-636217","volume":"125","author":"S Grant","year":"2015","unstructured":"Grant S. ATRA and ATO team up against NPM1. Blood. 2015;125:3369\u201371.","journal-title":"Blood"},{"key":"2764_CR37","doi-asserted-by":"publisher","first-page":"2351","DOI":"10.1038\/s41375-022-01666-2","volume":"36","author":"R Ranieri","year":"2022","unstructured":"Ranieri R, Pianigiani G, Sciabolacci S, Perriello VM, Marra A, Cardinali V, et al. Current status and future perspectives in targeted therapy of NPM1-mutated AML. Leukemia. 2022;36:2351\u201367.","journal-title":"Leukemia"},{"key":"2764_CR38","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1007\/s12185-019-02651-9","volume":"110","author":"M Duchmann","year":"2019","unstructured":"Duchmann M, Itzykson R. Clinical update on hypomethylating agents. Int J Hematol. 2019;110:161\u20139.","journal-title":"Int J Hematol"},{"key":"2764_CR39","doi-asserted-by":"crossref","unstructured":"Kubasch AS, Platzbecker U Beyond the Edge of Hypomethylating Agents: Novel Combination Strategies for Older Adults with Advanced MDS and AML. Cancers (Basel). 2018;10.","DOI":"10.3390\/cancers10060158"},{"key":"2764_CR40","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-19119-8","volume":"11","author":"K Morita","year":"2020","unstructured":"Morita K, Wang F, Jahn K, Hu T, Tanaka T, Sasaki Y, et al. Clonal evolution of acute myeloid leukemia revealed by high-throughput single-cell genomics. Nat Commun. 2020;11:5327.","journal-title":"Nat Commun"},{"key":"2764_CR41","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1038\/s41586-020-2864-x","volume":"587","author":"LA Miles","year":"2020","unstructured":"Miles LA, Bowman RL, Merlinsky TR, Csete IS, Ooi AT, Durruthy-Durruthy R, et al. Single-cell mutation analysis of clonal evolution in myeloid malignancies. Nature. 2020;587:477\u201382.","journal-title":"Nature"},{"key":"2764_CR42","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1038\/s41571-021-00509-w","volume":"18","author":"H Dohner","year":"2021","unstructured":"Dohner H, Wei AH, Lowenberg B. Towards precision medicine for AML. Nat Rev Clin Oncol. 2021;18:577\u201390.","journal-title":"Nat Rev Clin Oncol"}],"container-title":["Leukemia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41375-025-02764-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41375-025-02764-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41375-025-02764-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T19:03:54Z","timestamp":1767985434000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41375-025-02764-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,27]]},"references-count":42,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1]]}},"alternative-id":["2764"],"URL":"https:\/\/doi.org\/10.1038\/s41375-025-02764-7","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-6523399\/v1","asserted-by":"object"}]},"ISSN":["0887-6924","1476-5551"],"issn-type":[{"value":"0887-6924","type":"print"},{"value":"1476-5551","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,27]]},"assertion":[{"value":"24 April 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 August 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 September 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 October 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"Patient samples were taken following informed consent and in accordance with the Declaration of Helsinki. The local ethics committee (No. 334\/09 and No. 221\/14) approved the study protocol. All patient samples consisted of more than 90% leukemic blasts. Anonymized samples from HDs were obtained from the German Red Cross in Ulm, processed by ficollization (Pan Biotech, Aidenbach, Germany) and cryopreserved.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics"}}]}}