{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:58:06Z","timestamp":1792789086288,"version":"4.5.0"},"reference-count":86,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T00:00:00Z","timestamp":1790899200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T00:00:00Z","timestamp":1790899200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Hyundai Hope on Wheels Scholar Grant","id":[{"id":"https:\/\/ror.org\/01f6q3121","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Children\u2019s Healthcare of Atlanta","id":[{"id":"https:\/\/ror.org\/050fhx250","id-type":"ROR","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/050fhx250","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Winship Cancer Institute of Emory University","id":[{"id":"https:\/\/ror.org\/03czfpz43","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Winship Cancer Institute of Emory University","id":[{"id":"https:\/\/ror.org\/03czfpz43","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Atlanta Pediatric Scholars Program","award":["K12HD072245"],"award-info":[{"award-number":["K12HD072245"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Acute myeloid leukemia (AML) remains the deadliest form of leukemia in children and adults despite therapeutic advances in recent decades. Chimeric antigen receptor (CAR) T-cell therapy is one such therapeutic approach that has been explored preclinically and clinically in AML; however, its efficacy is limited by antigen heterogeneity. To overcome this roadblock, we propose a dual-targeting CAR T-cell strategy, targeting the AML-associated antigens CD33 and CD70. Methods: To recapitulate tumor heterogeneity, we genetically edited the AML cell line Molm-13 using CRISPR-Cas9 to generate distinct sublines, namely CD33+\/CD70\u2212, CD33\u2212\/CD70+, and CD33+\/CD70+. Two dual-targeting CAR T-cell approaches were developed: a \u201cpooled\u201d product, in which CAR T cells directed towards CD33 or CD70 are combined and co-administered, and a \u201cco-transduced\u201d product, wherein one population of T cells is transduced with both CD33-CAR- and CD70-CAR-encoding viral vectors. Results: Pooled and co-transduced products demonstrated potent cytotoxicity against all Molm-13 populations, whereas single-antigen CAR approaches were not as effective when their respective target antigen was absent. Mice engrafted with CD33\/CD70 heterogeneous Molm-13 cells were treated with pooled or co-transduced CD33\/CD70 CAR T cells. Both groups exhibited a significant survival advantage over the untreated group, with the co-transduced approach showing a statistically significant advantage over the pooled group. Conclusions: In summary, engineering one T cell to express both CARs yielded superior cytotoxicity when targeting a heterogeneous AML blast population.<\/jats:p>","DOI":"10.3390\/cancers18193183","type":"journal-article","created":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T11:21:49Z","timestamp":1790940109000},"page":"3183","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Developing a Dual-Targeting CD33\/CD70 CAR T-Cell Strategy Against Acute Myeloid Leukemia to Overcome Tumor Heterogeneity"],"prefix":"10.3390","volume":"18","author":[{"given":"Emily C.","family":"Sullivan","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA"},{"name":"Aflac Cancer and Blood Disorders Center, Children\u2019s Healthcare of Atlanta, Atlanta, GA 30329, USA"},{"name":"Molecular and Systems Pharmacology Graduate Program, Graduate Division of Biological and Biomedical Sciences, Emory University, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6073-9876","authenticated-orcid":false,"given":"Nabil","family":"Saleem","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA"},{"name":"Aflac Cancer and Blood Disorders Center, Children\u2019s Healthcare of Atlanta, Atlanta, GA 30329, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-4801-4798","authenticated-orcid":false,"given":"Areeba A.","family":"Hashmi","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA"},{"name":"Aflac Cancer and Blood Disorders Center, Children\u2019s Healthcare of Atlanta, Atlanta, GA 30329, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7948-0072","authenticated-orcid":false,"given":"Kristopher A.","family":"Knight","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA"},{"name":"Aflac Cancer and Blood Disorders Center, Children\u2019s Healthcare of Atlanta, Atlanta, GA 30329, USA"},{"name":"Molecular and Systems Pharmacology Graduate Program, Graduate Division of Biological and Biomedical Sciences, Emory University, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Austre Y.","family":"Schiaffino Bustamante","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA"},{"name":"Aflac Cancer and Blood Disorders Center, Children\u2019s Healthcare of Atlanta, Atlanta, GA 30329, USA"},{"name":"Cancer Biology Graduate Program, Graduate Division of Biological and Biomedical Sciences, Laney Graduate School, Emory University, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1839-1535","authenticated-orcid":false,"given":"Ahmed A.","family":"Aljudi","sequence":"additional","affiliation":[{"name":"Department of Pathology, Children\u2019s Healthcare of Atlanta, Atlanta, GA 30329, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"given":"Brandon J.","family":"Fanelli","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA"},{"name":"Aflac Cancer and Blood Disorders Center, Children\u2019s Healthcare of Atlanta, Atlanta, GA 30329, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2903-9542","authenticated-orcid":false,"given":"Sunil S.","family":"Raikar","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA"},{"name":"Aflac Cancer and Blood Disorders Center, Children\u2019s Healthcare of Atlanta, Atlanta, GA 30329, USA"},{"name":"Molecular and Systems Pharmacology Graduate Program, Graduate Division of Biological and Biomedical Sciences, Emory University, Atlanta, GA 30322, USA"},{"name":"Cancer Biology Graduate Program, Graduate Division of Biological and Biomedical Sciences, Laney Graduate School, Emory University, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,10,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e2300229","DOI":"10.1200\/GO.23.00229","article-title":"Burden of AML, 1990-2019: Estimates From the Global Burden of Disease Study","volume":"9","author":"Jani","year":"2023","journal-title":"JCO Glob. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Tseng, S., Lee, M.E., and Lin, P.C. (2023). A Review of Childhood Acute Myeloid Leukemia: Diagnosis and Novel Treatment. Pharmaceuticals, 16.","DOI":"10.3390\/ph16111614"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e572","DOI":"10.1097\/HS9.0000000000000572","article-title":"Treatment for Relapsed\/Refractory Acute Myeloid Leukemia","volume":"5","author":"Thol","year":"2021","journal-title":"Hemasphere"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1038\/s41408-024-01143-2","article-title":"Current status and research directions in acute myeloid leukemia","volume":"14","author":"Kantarjian","year":"2024","journal-title":"Blood Cancer J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1002\/ajh.27625","article-title":"Acute Myeloid Leukemia: 2025 Update on Diagnosis, Risk-Stratification, and Management","volume":"100","author":"Shimony","year":"2025","journal-title":"Am. J. Hematol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1182\/blood.2022016867","article-title":"Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN","volume":"140","author":"Wei","year":"2022","journal-title":"Blood"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e30584","DOI":"10.1002\/pbc.30584","article-title":"Children\u2019s Oncology Group\u2019s 2023 blueprint for research: Myeloid neoplasms","volume":"70","author":"Cooper","year":"2023","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2275","DOI":"10.3324\/haematol.2022.281106","article-title":"Relapsed pediatric acute myeloid leukaemia: State-of-the-art in 2023","volume":"108","author":"Egan","year":"2023","journal-title":"Haematologica"},{"key":"ref_9","first-page":"124","article-title":"Outcomes of patients with relapsed or refractory acute myeloid leukemia: A population-based real-world study","volume":"10","author":"Brandwein","year":"2020","journal-title":"Am. J. Blood Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2196482","DOI":"10.1080\/16078454.2023.2196482","article-title":"A review of treatment options employed in relapsed\/refractory AML","volume":"28","author":"Jiffry","year":"2023","journal-title":"Hematology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1182\/blood.2023022481","article-title":"How I treat refractory and relapsed acute myeloid leukemia","volume":"143","author":"Thol","year":"2024","journal-title":"Blood"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"5","DOI":"10.2174\/1389201019666180418095526","article-title":"CAR T-cell Therapy: A New Era in Cancer Immunotherapy","volume":"19","author":"Miliotou","year":"2018","journal-title":"Curr. Pharm. Biotechnol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1038\/s41571-019-0297-y","article-title":"Engineering strategies to overcome the current roadblocks in CAR T cell therapy","volume":"17","author":"Rafiq","year":"2020","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"224ra25","DOI":"10.1126\/scitranslmed.3008226","article-title":"Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia","volume":"6","author":"Davila","year":"2014","journal-title":"Sci. Transl. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3312","DOI":"10.1182\/blood-2016-02-629063","article-title":"CD19-targeted CAR T-cell therapeutics for hematologic malignancies: Interpreting clinical outcomes to date","volume":"127","author":"Park","year":"2016","journal-title":"Blood"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"6185","DOI":"10.1158\/1078-0432.CCR-18-0426","article-title":"A Phase I\/IIa Trial Using CD19-Targeted Third-Generation CAR T Cells for Lymphoma and Leukemia","volume":"24","author":"Enblad","year":"2018","journal-title":"Clin. Cancer Res."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Petersen, C.T., and Krenciute, G. (2019). Next Generation CAR T Cells for the Immunotherapy of High-Grade Glioma. Front. Oncol., 9.","DOI":"10.3389\/fonc.2019.00069"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Wang, A.X., Ong, X.J., D\u2019Souza, C., Neeson, P.J., and Zhu, J.J. (2023). Combining chemotherapy with CAR-T cell therapy in treating solid tumors. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1140541"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2378543","DOI":"10.1080\/21645515.2024.2378543","article-title":"Approved CAR-T therapies have reproducible efficacy and safety in clinical practice","volume":"20","author":"Waghela","year":"2024","journal-title":"Hum. Vaccin. Immunother."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e010709","DOI":"10.1136\/jitc-2024-010709","article-title":"Prior chemotherapy deteriorates T-cell quality for CAR T-cell therapy in B-cell non-Hodgkin\u2019s lymphoma","volume":"13","author":"Herzberg","year":"2025","journal-title":"J. Immunother. Cancer"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1038\/s41392-025-02269-w","article-title":"CAR-T cell therapy for cancer: Current challenges and future directions","volume":"10","author":"Zugasti","year":"2025","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1186\/s13045-026-01833-3","article-title":"A phase 1 trial of CD123-directed chimeric antigen receptor T-cell therapy in adults with relapsed\/refractory acute myeloid leukemia or blastic plasmacytoid dendritic cell neoplasm","volume":"19","author":"Budde","year":"2026","journal-title":"J. Hematol. Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2343","DOI":"10.1182\/blood-2013-09-529537","article-title":"Preclinical targeting of human acute myeloid leukemia and myeloablation using chimeric antigen receptor-modified T cells","volume":"123","author":"Gill","year":"2014","journal-title":"Blood"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1097\/MOH.0000000000000190","article-title":"T cells expressing CD123 chimeric antigen receptors for treatment of acute myeloid leukemia","volume":"22","author":"Mardiros","year":"2015","journal-title":"Curr. Opin. Hematol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2202","DOI":"10.1016\/j.ymthe.2017.05.024","article-title":"Treatment of Acute Myeloid Leukemia with T Cells Expressing Chimeric Antigen Receptors Directed to C-type Lectin-like Molecule 1","volume":"25","author":"Tashiro","year":"2017","journal-title":"Mol. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s13045-017-0553-5","article-title":"CAR-T cells targeting CLL-1 as an approach to treat acute myeloid leukemia","volume":"11","author":"Wang","year":"2018","journal-title":"J. Hematol. Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3549","DOI":"10.1158\/1078-0432.CCR-20-4543","article-title":"Anti-CLL1 Chimeric Antigen Receptor T-Cell Therapy in Children with Relapsed\/Refractory Acute Myeloid Leukemia","volume":"27","author":"Zhang","year":"2021","journal-title":"Clin. Cancer Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1182\/blood-2023-179667","article-title":"CD33 CAR T-Cells (CD33CART) for Children and Young Adults with Relapsed\/Refractory AML: Dose-Escalation Results from a Phase I\/II Multicenter Trial","volume":"142","author":"Shah","year":"2023","journal-title":"Blood"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1084\/jem.20152008","article-title":"CD70\/CD27 signaling promotes blast stemness and is a viable therapeutic target in acute myeloid leukemia","volume":"214","author":"Riether","year":"2017","journal-title":"J. Exp. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1182\/blood.2020008221","article-title":"CD70-specific CAR T cells have potent activity against acute myeloid leukemia without HSC toxicity","volume":"138","author":"Sauer","year":"2021","journal-title":"Blood"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Wu, G., Guo, S., Luo, Q., Wang, X., Deng, W., Ouyang, G., Pu, J.J., Lei, W., and Qian, W. (2023). Preclinical evaluation of CD70-specific CAR T cells targeting acute myeloid leukemia. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1093750"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e937","DOI":"10.1097\/HS9.0000000000000937","article-title":"CAR-T in the Treatment of Acute Myeloid Leukemia: Barriers and How to Overcome Them","volume":"7","author":"Vanhooren","year":"2023","journal-title":"Hemasphere"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1016\/j.cll.2021.04.005","article-title":"Antigen Loss after Targeted Immunotherapy in Hematological Malignancies","volume":"41","author":"Zhou","year":"2021","journal-title":"Clin. Lab. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"20406207251326802","DOI":"10.1177\/20406207251326802","article-title":"Recent advances of CAR-T cells in acute myeloid leukemia","volume":"16","author":"Deng","year":"2025","journal-title":"Ther. Adv. Hematol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1186\/s40164-025-00726-4","article-title":"Emerging strategies in CAR-T cell therapy for acute myeloid leukemia: Overcoming heterogeneity and improving safety through dual-antigen targeting","volume":"14","author":"Mutis","year":"2025","journal-title":"Exp. Hematol. Oncol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1016\/j.ccell.2017.09.004","article-title":"Integrating Proteomics and Transcriptomics for Systematic Combinatorial Chimeric Antigen Receptor Therapy of AML","volume":"32","author":"Perna","year":"2017","journal-title":"Cancer Cell"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e218","DOI":"10.1038\/bcj.2014.39","article-title":"Distribution and levels of cell surface expression of CD33 and CD123 in acute myeloid leukemia","volume":"4","author":"Ehninger","year":"2014","journal-title":"Blood Cancer J."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1182\/blood.2023023210","article-title":"CD70 CAR T cells secreting an anti-CD33\/anti-CD3 dual-targeting antibody overcome antigen heterogeneity in AML","volume":"145","author":"Silva","year":"2025","journal-title":"Blood"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Dean, E.A. (2026). T-cell exhaustion due to BiTE therapy in multiple myeloma: Mitigating infectious risks through treatment-free intervals. Front. Immunol., 17.","DOI":"10.3389\/fimmu.2026.1705345"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"101031","DOI":"10.1016\/j.medj.2026.101031","article-title":"T cell exhaustion in bi- and trispecific T cell engager therapy in hematologic malignancies: Mechanisms and implications","volume":"7","author":"Muth","year":"2026","journal-title":"Med"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1182\/bloodadvances.2025018168","article-title":"FLT3-directed BiTE molecules vs CAR T cells in AML: Costimulatory signals mitigate T-cell exhaustion","volume":"10","author":"Rohrbacher","year":"2026","journal-title":"Blood Adv."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"D917","DOI":"10.1093\/nar\/gkv1101","article-title":"BloodSpot: A database of gene expression profiles and transcriptional programs for healthy and malignant haematopoiesis","volume":"44","author":"Bagger","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1082","DOI":"10.1158\/2159-8290.CD-20-1230","article-title":"St. Jude Cloud: A Pediatric Cancer Genomic Data-Sharing Ecosystem","volume":"11","author":"McLeod","year":"2021","journal-title":"Cancer Discov."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2424","DOI":"10.1182\/blood-2012-10-462440","article-title":"Significance of FAB subclassification of \u201cacute myeloid leukemia, NOS\u201d in the 2008 WHO classification: Analysis of 5848 newly diagnosed patients","volume":"121","author":"Walter","year":"2013","journal-title":"Blood"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1002\/cyto.b.21773","article-title":"Comparison of Volumetric and Bead-Based Counting of CD34 Cells by Single-Platform Flow Cytometry","volume":"96","author":"Saraiva","year":"2019","journal-title":"Cytom. B Clin. Cytom."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e1792","DOI":"10.1038\/cddis.2015.162","article-title":"T-cell exhaustion in the tumor microenvironment","volume":"6","author":"Jiang","year":"2015","journal-title":"Cell Death Dis."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.4049\/jimmunol.148.4.1149","article-title":"Chimeric and humanized antibodies with specificity for the CD33 antigen","volume":"148","author":"Co","year":"1992","journal-title":"J. Immunol."},{"key":"ref_48","unstructured":"Ho, D.T., Olafsen, T., Agahi, G., and Gudas, J. (2014). Antigen Binding Constructs to CD70, WIPO. WO2014158821A1."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1016\/j.ccell.2022.04.001","article-title":"Non-cleavable hinge enhances avidity and expansion of CAR-T cells for acute myeloid leukemia","volume":"40","author":"Leick","year":"2022","journal-title":"Cancer Cell"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1146\/annurev.immunol.22.012703.104702","article-title":"Central memory and effector memory T cell subsets: Function, generation, and maintenance","volume":"22","author":"Sallusto","year":"2004","journal-title":"Annu. Rev. Immunol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3552","DOI":"10.1038\/s41467-024-47799-z","article-title":"CAR affinity modulates the sensitivity of CAR-T cells to PD-1\/PD-L1-mediated inhibition","volume":"15","author":"Marzal","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/0145-2126(84)90001-8","article-title":"A monoclonal antibody reactive with normal and leukemic human myeloid progenitor cells","volume":"8","author":"Griffin","year":"1984","journal-title":"Leuk. Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1182\/blood.V96.2.483.014k40_483_490","article-title":"Myeloid specific human CD33 is an inhibitory receptor with differential ITIM function in recruiting the phosphatases SHP-1 and SHP-2","volume":"96","author":"Paul","year":"2000","journal-title":"Blood"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Molica, M., Perrone, S., Mazzone, C., Niscola, P., Cesini, L., Abruzzese, E., and de Fabritiis, P. (2021). CD33 Expression and Gentuzumab Ozogamicin in Acute Myeloid Leukemia: Two Sides of the Same Coin. Cancers, 13.","DOI":"10.3390\/cancers13133214"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1182\/blood.2021011694","article-title":"How I treat pediatric acute myeloid leukemia","volume":"138","author":"Rubnitz","year":"2021","journal-title":"Blood"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Liu, J., Tong, J., and Yang, H. (2022). Targeting CD33 for acute myeloid leukemia therapy. BMC Cancer, 22.","DOI":"10.1186\/s12885-021-09116-5"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"3282","DOI":"10.1038\/s41375-021-01232-2","article-title":"Autologous CD33-CAR-T cells for treatment of relapsed\/refractory acute myelogenous leukemia","volume":"35","author":"Tambaro","year":"2021","journal-title":"Leukemia"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"e003149","DOI":"10.1136\/jitc-2021-003149","article-title":"Systematic preclinical evaluation of CD33-directed chimeric antigen receptor T cell immunotherapy for acute myeloid leukemia defines optimized construct design","volume":"9","author":"Qin","year":"2021","journal-title":"J. Immunother. Cancer"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1182\/blood.2024027364","article-title":"Novel CAR T cells to combat antigen escape in AML","volume":"145","year":"2025","journal-title":"Blood"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Xu, X., Sun, Q., Liang, X., Chen, Z., Zhang, X., Zhou, X., Li, M., Tu, H., Liu, Y., and Tu, S. (2019). Mechanisms of Relapse After CD19 CAR T-Cell Therapy for Acute Lymphoblastic Leukemia and Its Prevention and Treatment Strategies. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.02664"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"117252","DOI":"10.1016\/j.biopha.2024.117252","article-title":"Antigen escape in CAR-T cell therapy: Mechanisms and overcoming strategies","volume":"178","author":"Lin","year":"2024","journal-title":"BioMed. Pharmacother."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"6518","DOI":"10.1200\/JCO.2024.42.16_suppl.6518","article-title":"Phase I study of functionally enhanced CD33 CAR T cells in patients with relapsed or refractory acute myeloid leukemia","volume":"42","author":"Pan","year":"2024","journal-title":"J. Clin. Oncol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1914","DOI":"10.1182\/blood.2025031053","article-title":"A phase 1\/2 study of donor-derived anti-CD33 CAR T-cell therapy (VCAR33) for relapsed\/refractory AML after allogeneic HCT","volume":"147","author":"Mushtaq","year":"2026","journal-title":"Blood"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/0092-8674(93)90133-B","article-title":"Molecular and biological characterization of a ligand for CD27 defines a new family of cytokines with homology to tumor necrosis factor","volume":"73","author":"Goodwin","year":"1993","journal-title":"Cell"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/s13046-021-02215-y","article-title":"The CD70-CD27 axis in oncology: The new kids on the block","volume":"41","author":"Flieswasser","year":"2022","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"e70400","DOI":"10.1002\/ctm2.70400","article-title":"CD70: An emerging target for integrated cancer diagnosis and therapy","volume":"15","author":"Hu","year":"2025","journal-title":"Clin. Transl. Med."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2331","DOI":"10.1007\/s00262-023-03422-6","article-title":"Preclinical development and evaluation of nanobody-based CD70-specific CAR T cells for the treatment of acute myeloid leukemia","volume":"72","author":"Cheng","year":"2023","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"3697","DOI":"10.1038\/s41591-024-03271-5","article-title":"Cytokine-mediated CAR T therapy resistance in AML","volume":"30","author":"Bhagwat","year":"2024","journal-title":"Nat. Med."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.gde.2016.03.011","article-title":"Genetic and epigenetic heterogeneity in acute myeloid leukemia","volume":"36","author":"Li","year":"2016","journal-title":"Curr. Opin. Genet. Dev."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1097\/BS9.0000000000000015","article-title":"Tumor heterogeneity of acute myeloid leukemia: Insights from single-cell sequencing","volume":"1","author":"Chen","year":"2019","journal-title":"Blood Sci."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"114260","DOI":"10.1016\/j.celrep.2024.114260","article-title":"Immunotherapeutic targeting of surfaceome heterogeneity in AML","volume":"43","author":"Bordeleau","year":"2024","journal-title":"Cell Rep."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1871","DOI":"10.1016\/j.ccell.2023.09.010","article-title":"Cooperative CAR targeting to selectively eliminate AML and minimize escape","volume":"41","author":"Haubner","year":"2023","journal-title":"Cancer Cell"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"2248826","DOI":"10.1080\/2162402X.2023.2248826","article-title":"CAR-T cells dual-target CD123 and NKG2DLs to eradicate AML cells and selectively target immunosuppressive cells","volume":"12","author":"Jin","year":"2023","journal-title":"Oncoimmunology"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1111\/ejh.14104","article-title":"Tandem bispecific CD123\/CLL-1 CAR-T cells exhibit specific cytolytic effector functions against human acute myeloid leukaemia","volume":"112","author":"Wang","year":"2024","journal-title":"Eur. J. Haematol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"101695","DOI":"10.1016\/j.tranon.2023.101695","article-title":"Bicistronic CAR-T cells targeting CD123 and CLL1 for AML to reduce the risk of antigen escape","volume":"34","author":"Xie","year":"2023","journal-title":"Transl. Oncol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"100751","DOI":"10.1016\/j.omto.2023.100751","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":"ref_77","first-page":"338","article-title":"The tandem CD33-CLL1 CAR-T as an approach to treat acute myeloid leukemia","volume":"23","author":"Wang","year":"2025","journal-title":"Blood Transfus."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1260419","DOI":"10.1126\/science.1260419","article-title":"Proteomics. Tissue-based map of the human proteome","volume":"347","author":"Fagerberg","year":"2015","journal-title":"Science"},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Gomez-Melero, S., Hassouneh, F., Vallejo-Bermudez, I.M., Aguera-Morales, E., Solana, R., and Caballero-Villarraso, J. (2025). Tandem CAR-T cell therapy: Recent advances and current challenges. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1546172"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"115973","DOI":"10.1016\/j.celrep.2025.115973","article-title":"CAR-T cells containing CD28 versus 4-1BB co-stimulatory domains show distinct metabolic profiles in patients","volume":"44","author":"Cook","year":"2025","journal-title":"Cell Rep."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"e20230903","DOI":"10.1084\/jem.20230903","article-title":"CAR-T cell manufacturing: Major process parameters and next-generation strategies","volume":"221","author":"Khericha","year":"2024","journal-title":"J. Exp. Med."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"114421","DOI":"10.1016\/j.addr.2022.114421","article-title":"Cellular kinetics: A clinical and computational review of CAR-T cell pharmacology","volume":"188","author":"Qi","year":"2022","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"eaei0875","DOI":"10.1126\/scitranslmed.aei0875","article-title":"A phase 1 feasibility trial of BE-CAR33, an \u201coff-the-shelf\u201d base-edited CAR33 T cell therapy for acute myeloid leukemia","volume":"18","author":"Georgiadis","year":"2026","journal-title":"Sci. Transl. Med."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"117325","DOI":"10.1016\/j.intimp.2026.117325","article-title":"Humanized CD70-targeted CAR-T cells with reduced fratricide demonstrate potent antitumor activity against AML and RCC","volume":"188","author":"Zhang","year":"2026","journal-title":"Int. Immunopharmacol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"3163","DOI":"10.1007\/s00262-023-03475-7","article-title":"Revealing the impact of CD70 expression on the manufacture and functions of CAR-70 T-cells based on single-cell transcriptomics","volume":"72","author":"Cheng","year":"2023","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1649","DOI":"10.1111\/bjh.19348","article-title":"The role of chimeric antigen receptor T cells targeting more than one antigen in the treatment of B-cell malignancies","volume":"204","author":"Brillembourg","year":"2024","journal-title":"Br. J. Haematol."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/19\/3183\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T04:17:55Z","timestamp":1791951475000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/19\/3183"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,2]]},"references-count":86,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2026,10]]}},"alternative-id":["cancers18193183"],"URL":"https:\/\/doi.org\/10.3390\/cancers18193183","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,2]]}}}