{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T13:22:36Z","timestamp":1784035356432,"version":"3.55.0"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T00:00:00Z","timestamp":1776902400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Chimeric antigen receptor T cell (CAR-T cell) therapy is an immunotherapy for acute leukemias utilizing recombinant receptors specific to antigens involved in T-cell function to direct tumor cell recognition and elimination. However, major limitations include relapse due to antigen escape and tumor heterogeneity, as well as on-target off-tumor effects. Bispecific CAR-T cells are developed to overcome these issues.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Method<\/jats:title>\n                    <jats:p>\n                      A literature search was conducted to identify relevant articles using three databases (PubMed, Scopus, ProQuest) between 2016 and 2025. Studies written in English and\n                      <jats:italic>in vivo<\/jats:italic>\n                      ,\n                      <jats:italic>in vitro<\/jats:italic>\n                      , and clinical trial research designs were included. Articles without complete data and case reports were excluded. The systematic review followed PRISMA guidelines.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Nine studies were included in the final synthesis. Bispecific CAR-T cell therapy was superior in tumor eradication and limiting adverse effects in both AML and ALL. CARs used in AML often targeted CD123 and CD33; development of more diverse targets, including cell signaling of tumor growth (FLT3, NKG2D, TIM3, FR\u03b2), addressed heterogeneity. CD19 was the most common CAR in ALL, additionally targeting CD22, CD20, and BAFF-R; addressing CD19-negative relapse was quite common. Phase I clinical trials were done for CD19\/CD22 bispecific CAR-T cells, proving effective with low incidence of cytokine release syndrome, neurotoxicity, or other adverse effects. Preclinical trials showed that bispecific CAR-T cells had longer\n                      <jats:italic>in vivo<\/jats:italic>\n                      persistence.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Bispecific CAR-T cell therapy is more effective in managing acute leukemias than conventional CAR-T cells. Future research should focus on developing diverse targets and advancing into clinical trials.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Systematic Review Registration<\/jats:title>\n                    <jats:p>\n                      Open Science Framework (OSF) Registries\n                      <jats:ext-link>https:\/\/osf.io\/<\/jats:ext-link>\n                      , registration DOI:\n                      <jats:ext-link>https:\/\/doi.org\/10.17605<\/jats:ext-link>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2026.1720483","type":"journal-article","created":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T04:22:17Z","timestamp":1776918137000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Exploring current evidence on bispecific CAR-T cell therapy for acute leukemias: a systematic review"],"prefix":"10.3389","volume":"16","author":[{"given":"Gabriela Valencia Putri","family":"Husodho","sequence":"first","affiliation":[{"name":"Faculty of Medicine, Universitas Diponegoro","place":["Semarang, Indonesia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anatalya Diah Ayu","family":"Kumalasari","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Universitas Diponegoro","place":["Semarang, Indonesia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agyta Hanifa","family":"Faiza","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Universitas Diponegoro","place":["Semarang, Indonesia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward Kurnia Setiawan","family":"Limijadi","sequence":"additional","affiliation":[{"name":"Department of Clinical Pathology, Faculty of Medicine, Universitas Diponegoro","place":["Semarang, Indonesia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meita","family":"Hendrianingtyas","sequence":"additional","affiliation":[{"name":"Department of Clinical Pathology, Faculty of Medicine, Universitas Diponegoro","place":["Semarang, Indonesia"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,23]]},"reference":[{"key":"B1","article-title":"Leukemia","volume-title":"StatPearls","author":"Chennamadhavuni","year":"2025"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3390\/cancers16244136","article-title":"Acute myeloid leukaemia and acute lymphoblastic leukaemia classification and metabolic characteristics for informing and advancing treatment","volume":"16","author":"Wemyss","year":"2024","journal-title":"Cancers (Basel)"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13092256","article-title":"Etiology of acute leukemia: a review","volume":"13","author":"Tebbi","year":"2021","journal-title":"Cancers (Basel)"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.72599","article-title":"Recent developments and challenges in the treatment of acute leukemia and myelodysplastic syndromes: a systematic review","volume":"16","author":"Rafiq","year":"2024","journal-title":"Cureus"},{"key":"B5","article-title":"Chimeric antigen receptor T-cell therapy [Homepage on the Internet","volume-title":"StatPearls","author":"Zhang","year":"2025"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.34172\/ipp.2025.41730","article-title":"In vitro anti-cancer potentiality of quince and dandelion leaves extract against leukemia cell lines and database retrieval expression of BCR ABL and TCR genes in leukemia","volume":"12","author":"Abdulrahman","year":"2024","journal-title":"Immunopathol Persa"},{"key":"B7","unstructured":"CAR T cells: Engineering immune cells to treat cancer - NCI\n          \n          \n          \n          2025"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2024.19462","article-title":"CAR T cells and T-cell therapies for cancer","volume":"332","author":"Brudno","year":"2024","journal-title":"JAMA"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3390\/vaccines11010165","article-title":"CAR T-cell immunotherapy treating T-ALL: challenges and opportunities","volume":"11","author":"Ren","year":"2023","journal-title":"Vaccines (Basel)"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.cd-15-1020","article-title":"Convergence of acquired mutations and alternative splicing of CD19 enables resistance to CART-19 immunotherapy","volume":"5","author":"Sotillo","year":"2015","journal-title":"Cancer Discov"},{"key":"B11","doi-asserted-by":"publisher","first-page":"659","DOI":"10.1038\/s41408-017-0023-x","article-title":"CD19-negative relapse of pediatric B-cell precursor acute lymphoblastic leukemia following blinatumomab treatment","volume":"7","author":"Mejstr\u00edkov\u00e1","year":"2017","journal-title":"Blood Cancer J"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1165870","article-title":"Failure of ALL recognition by CAR T cells: a review of CD 19-negative relapses after anti-CD 19 CAR-T treatment in B-ALL","volume":"14","author":"Aparicio-P\u00e9rez","year":"2023","journal-title":"Front Immunol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.18369","article-title":"Recent advances in CAR\u2010T cell therapy for acute myeloid leukaemia","volume":"28","author":"Gao","year":"2024","journal-title":"J Cell Mol Med"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2024.113166","article-title":"Advancements in the design and function of bispecific CAR-T cells targeting B cell-associated tumor antigens","volume":"142","author":"Sima","year":"2024","journal-title":"Int Immunopharmacol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1546172","article-title":"Tandem CAR-T cell therapy: recent advances and current challenges","volume":"16","author":"G\u00f3mez-Melero","year":"2025","journal-title":"Front Immunol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1007\/s11060-021-03902-8","article-title":"Using chimeric antigen receptor T-cell therapy to fight glioblastoma multiforme: past, present and future developments","volume":"156","author":"Soler","year":"2022","journal-title":"J Neuro-Oncol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3390\/ijms26083920","article-title":"Immunotherapy in breast cancer: Beyond immune checkpoint inhibitors","volume":"26","author":"Choi","year":"2025","journal-title":"Int J Mol Sci"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1093\/immadv\/ltae005","article-title":"Bispecific T-cell engagers for the recruitment of T cells in solid tumors: a literature review","volume":"5","author":"Dewaele","year":"2025","journal-title":"Immunother Adv"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.glmedi.2023.100046","article-title":"Formulating research questions for evidence-based studies","volume":"2","author":"Hosseini","year":"2024","journal-title":"J Medicine Surgery Public Health"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-020-00856-8","article-title":"Bispecific CAR-T cells targeting both CD19 and CD22 for therapy of adults with relapsed or refractory B cell acute lymphoblastic leukemia","volume":"13","author":"Dai","year":"2020","journal-title":"J Hematol Oncol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-021-01436-0","article-title":"CAR T cells with dual targeting of CD19 and CD22 in adult patients with recurrent or refractory B cell Malignancies: a phase 1 trial","volume":"27","author":"Spiegel","year":"2021","journal-title":"Nat Med"},{"key":"B22","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1186\/s12943-022-01541-9","article-title":"A novel approach for relapsed\/refractory FLT3mut+ acute myeloid leukaemia: synergistic effect of the combination of bispecific FLT3scFv\/NKG2D-CAR T cells and gilteritinib","volume":"21","author":"Li","year":"2022","journal-title":"Mol Cancer"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1186\/s40425-017-0246-1","article-title":"A tandem CD19\/CD20 CAR lentiviral vector drives on-target and off-target antigen modulation in leukemia cell lines","volume":"5","author":"Schneider","year":"2017","journal-title":"J Immunotherapy Cancer"},{"key":"B24","doi-asserted-by":"publisher","first-page":"100751","DOI":"10.1182\/blood-2022-163299","article-title":"Bispecific CD33\/CD123 targeted chimeric antigen receptor T cells for the treatment of acute myeloid leukemia","volume":"31","author":"Boucher","year":"2023","journal-title":"Mol Ther Oncolytics"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-021-01477-x","article-title":"CD19\/BAFF-R dual-targeted CAR T cells for the treatment of mixed antigen-negative variants of acute lymphoblastic leukemia","volume":"36","author":"Wang","year":"2022","journal-title":"Leukemia"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1080\/2162402x.2025.2458843","article-title":"Dual nanobody-redirected and bi-specific CD13\/TIM3 CAR T cells eliminate AML xenografts without toxicity to human HSCs","volume":"14","author":"Zhang","year":"2025","journal-title":"OncoImmunology"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.22074\/cellj.2021.7314","article-title":"Design and production an effective bispecific tandem chimeric antigen receptor on T cells against CD123 and folate receptor \u00df towards B-acute myeloid leukaemia blasts","volume":"23","author":"Ghamari","year":"2021","journal-title":"Cell J"},{"key":"B28","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1111\/ejh.14104","article-title":"Tandem bispecific CD123 \/ CLL \u20101 CAR\u2010T cells exhibit specific cytolytic effector functions against human acute myeloid leukaemia","volume":"112","author":"Wang","year":"2024","journal-title":"Eur J Haematology"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.34172\/ipp.2025.43799","article-title":"CD34+CD38-stem cells and CD34+CD38+progenitor cells as markers of chemotherapy response in acute myeloid leukemia patients","volume":"11","author":"Fergany","year":"2025","journal-title":"Immunopathologia Persa"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2019002779","article-title":"Bispecific and split CAR T cells targeting CD13 and TIM3 eradicate acute myeloid leukemia","volume":"135","author":"He","year":"2020","journal-title":"Blood"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2024024063","article-title":"Honing CAR T cells to tackle acute myeloid leukemia","volume":"145","author":"Haubner","year":"2025","journal-title":"Blood"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13133214","article-title":"CD33 expression and gentuzumab ozogamicin in acute myeloid leukemia: two sides of the same coin","volume":"13","author":"Molica","year":"2021","journal-title":"Cancers (Basel)"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.14694\/edbook_am.2015.35.e360","article-title":"CD19 CAR therapy for acute lymphoblastic leukemia","volume":"35","author":"Sadelain","year":"2015","journal-title":"Am Soc Clin Oncol Educ Book"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbmt.2018.12.756","article-title":"Cytokine release syndrome with chimeric antigen receptor T cell therapy","volume":"25","author":"Frey","year":"2019","journal-title":"Biol Blood Marrow Transplant"},{"key":"B35","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1186\/s13045-019-0741-6","article-title":"Haploidentical CD19\/CD22 bispecific CAR-T cells induced MRD-negative remission in a patient with relapsed and refractory adult B-ALL after haploidentical hematopoietic stem cell transplantation","volume":"12","author":"Jia","year":"2019","journal-title":"J Hematol Oncol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa1709866","article-title":"Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia","volume":"378","author":"Maude","year":"2018","journal-title":"N Engl J Med"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2013.154","article-title":"Persistence and efficacy of second generation CAR T cell against the LeY antigen in acute myeloid leukemia","volume":"21","author":"Ritchie","year":"2013","journal-title":"Mol Ther"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.cd-17-0698","article-title":"Endothelial activation and blood\u2013brain barrier disruption in neurotoxicity after adoptive immunotherapy with CD19 CAR-T cells | Cancer Discovery | American Association for Cancer Research","volume":"7","author":"Gust","year":"2017","journal-title":"Cancer Discov"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-12-474056","article-title":"T cells expressing CD123-specific chimeric antigen receptors exhibit specific cytolytic effector functions and antitumor effects against human acute myeloid leukemia","volume":"122","author":"Mardiros","year":"2013","journal-title":"Blood"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.2147\/ott.s205678","article-title":"IFN-\u03b3 and TNF-\u03b1 aggravate endothelial damage caused by CD123-targeted CAR T cell","volume":"12","author":"Sun","year":"2019","journal-title":"Onco Targets Ther"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1720483\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T04:22:19Z","timestamp":1776918139000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1720483\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,23]]},"references-count":40,"alternative-id":["10.3389\/fonc.2026.1720483"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2026.1720483","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,23]]},"article-number":"1720483"}}