T-Cell Responses and T-Cell-Based Therapy in Acute Myeloid Leukemia

Abstract

Acute myeloid leukemia (AML) is a common and aggressive blood cancer characterized by the abnormal growth of primitive bone marrow cells. Genetic mutations prevent normal differentiation into blood components. Potential causes include environmental factors, radiation, and viral infections. Research on AML is essential for enhancing our understanding of the disease, facilitating the development of effective treatments, and improving early diagnostic methods to ultimately increase patient survival rates and quality of life. This study focused on the T-cell immune response and T-cell immunotherapy in AML. We collected CD8+ T cells, CD4 + T cells, Natural killer T (NKT) cells, and γδ T cells among the T cells and analyzed the roles that they play in AML. Long-term disease control in AML requires a variety of immunotherapies, including T-cell receptor-engineered T cells (TCR-T), chimeric antigen receptor T-cell therapy (CAR-T), and T-cell immune checkpoint inhibitors. We discuss these treatments and try to find better treatments for AML in the future.

Keywords

T cell / Immunotherapy / Acute myeloid leukemia / T-cell immune response

References

[1] De Kouchkovsky I, Abdul-Hay M. Acute myeloid leukemia: a comprehensive review and 2016 update. Blood Cancer Journal., 2016, 6(7): e441-e441

[2] Liu H. Emerging agents and regimens for AML. J Hematol Oncol., 2021, 14(1): 49

[3] Kayser S, Levis MJ. The clinical impact of the molecular landscape of acute myeloid leukemia. Haematologica., 2023, 108(2308-320

[4] Haferlach T. Advancing leukemia diagnostics: Role of Next Generation Sequencing (NGS) in acute myeloid leukemia. Hematol Rep., 2020, 12(Suppl 1): 8957

[5] Bazinet A, Kantarjian HM. Moving toward individualized target-based therapies in acute myeloid leukemia. Ann Oncol., 2023, 34(2141-151

[6] Pelcovits A, Niroula R. Acute Myeloid Leukemia: A Review. R I Med J (2013). 2020;103(3):38–40.

[7] Yang X, Wang J. Precision therapy for acute myeloid leukemia. J Hematol Oncol., 2018, 11(1): 3

[8] Lamble AJ, Kosaka Y, Laderas T, et al.. Reversible suppression of T cell function in the bone marrow microenvironment of acute myeloid leukemia. Proc Natl Acad Sci U S A., 2020, 117(2514331-14341

[9] Liu G, Rui W, Zhao X, et al.. Enhancing CAR-T cell efficacy in solid tumors by targeting the tumor microenvironment. Cell Mol Immunol., 2021, 18(5): 1085-1095

[10] Vago L, Gojo I. Immune escape and immunotherapy of acute myeloid leukemia. J Clin Invest., 2020, 130(4): 1552-1564

[11] Ranieri R, Pianigiani G, Sciabolacci S, et al.. Current status and future perspectives in targeted therapy of NPM1-mutated AML. Leukemia., 2022, 36(10): 2351-2367

[12] Xu L, Liu L, Yao D, et al.. PD-1 and TIGIT Are Highly Co-Expressed on CD8(+) T Cells in AML Patient Bone Marrow. Front Oncol., 2021, 11 686156

[13] Zhou W, Yu J, Li Y, et al.. Neoantigen-specific TCR-T cell-based immunotherapy for acute myeloid leukemia. Exp Hematol Oncol., 2022, 11(1): 100

[14] Hofmann S, Gotz M, Schneider V, et al.. Donor lymphocyte infusion induces polyspecific CD8(+) T-cell responses with concurrent molecular remission in acute myeloid leukemia with NPM1 mutation. J Clin Oncol., 2013, 31(3e44-47

[15] van der Lee DI, Reijmers RM, Honders MW, et al.. Mutated nucleophosmin 1 as immunotherapy target in acute myeloid leukemia. J Clin Invest., 2019, 129(2): 774-785

[16] Sun Q, Zhang X, Wang L, et al.. T-cell receptor gene therapy targeting melanoma-associated antigen-A4 by silencing of endogenous TCR inhibits tumor growth in mice and human. Cell Death Dis., 2019, 10(7): 475

[17] Mueller KT, Maude SL, Porter DL, et al.. Cellular kinetics of CTL019 in relapsed/refractory B-cell acute lymphoblastic leukemia and chronic lymphocytic leukemia. Blood., 2017, 130(212317-2325

[18] Haslauer T, Greil R, Zaborsky N, et al.. CAR T-Cell Therapy in Hematological Malignancies. Int J Mol Sci., 2021, 22(16): 8996

[19] Haubner S, Mansilla-Soto J, Nataraj S, et al.. Cooperative CAR targeting to selectively eliminate AML and minimize escape. Cancer Cell., 2023, 41(111871-1891.e1876

[20] Gao XN, Su YF, Li MY, et al.. Single-center phase 2 study of PD-1 inhibitor combined with DNA hypomethylation agent + CAG regimen in patients with relapsed/refractory acute myeloid leukemia. Cancer Immunol Immunother., 2023, 72(8): 2769-2782

[21] Goswami M, Gui G, Dillon LW, et al.. Pembrolizumab and decitabine for refractory or relapsed acute myeloid leukemia. J Immunother Cancer., 2022, 10(1 e003392

[22] Tabata R, Chi S, Yuda J, et al.. Emerging Immunotherapy for Acute Myeloid Leukemia. Int J Mol Sci., 2021, 22(4): 1994

[23] Bassani B, Simonetti G, Cancila V, et al.. ZEB1 shapes AML immunological niches, suppressing CD8 T cell activity while fostering Th17 cell expansion. Cell Rep., 2024, 43(2 113794

[24] Desai PN, Wang B, Fonseca A, et al. Single-Cell Profiling of CD8+ T Cells in Acute Myeloid Leukemia Reveals a Continuous Spectrum of Differentiation and Clonal Hyperexpansion. Cancer Immunol Res. 2023:CIR-22-0961.

[25] Liu Y, Bewersdorf JP, Stahl M, et al.. Immunotherapy in acute myeloid leukemia and myelodysplastic syndromes: The dawn of a new era?. Blood Rev., 2019, 34: 67-83

[26] Zhou H, Jia B, Annageldiyev C, et al.. CD26(low)PD-1(+) CD8 T cells are terminally exhausted and associated with leukemia progression in acute myeloid leukemia. Front Immunol., 2023, 14: 1169144

[27] Chen Y, Feng Z, Kuang X, et al.. Increased lactate in AML blasts upregulates TOX expression, leading to exhaustion of CD8(+) cytolytic T cells. Am J Cancer Res., 2021, 11(115726-5742

[28] Feng Z, Fang Q, Kuang X, et al.. Clonal expansion of bone marrow CD8(+) T cells in acute myeloid leukemia patients at new diagnosis and after chemotherapy. Am J Cancer Res., 2020, 10(113973-3989

[29] Kato Y, Iwama A, Tadokoro Y, et al.. Selective activation of STAT5 unveils its role in stem cell self-renewal in normal and leukemic hematopoiesis. J Exp Med., 2005, 202(1): 169-179

[30] Huang ZW, Zhang XN, Zhang L, et al.. STAT5 promotes PD-L1 expression by facilitating histone lactylation to drive immunosuppression in acute myeloid leukemia. Signal Transduct Target Ther., 2023, 8(1): 391

[31] Deng M, Gui X, Kim J, et al.. LILRB4 signalling in leukaemia cells mediates T cell suppression and tumour infiltration. Nature., 2018, 562(7728605-609

[32] Li Z, Deng M, Huang F, et al.. LILRB4 ITIMs mediate the T cell suppression and infiltration of acute myeloid leukemia cells. Cell Mol Immunol., 2020, 17(3): 272-282

[33] Zhang J, Peng Y, He Y, et al.. GPX1-associated prognostic signature predicts poor survival in patients with acute myeloid leukemia and involves in immunosuppression. Biochim Biophys Acta Mol Basis Dis., 2022, 1868(1 166268

[34] Towers R, Trombello L, Fusenig M, et al.. Bone marrow-derived mesenchymal stromal cells obstruct AML-targeting CD8(+) clonal effector and CAR T-cell function while promoting a senescence-associated phenotype. Cancer Immunol Immunother., 2024, 73(1): 8

[35] Oh DY, Fong L. Cytotoxic CD4(+) T cells in cancer: Expanding the immune effector toolbox. Immunity., 2021, 54(122701-2711

[36] Scott EN, Gocher AM, Workman CJ, et al.. Regulatory T Cells: Barriers of Immune Infiltration Into the Tumor Microenvironment. Front Immunol., 2021, 12 702726

[37] Solis-Castillo LA, Garcia-Romo GS, Diaz-Rodriguez A, et al.. Tumor-infiltrating regulatory T cells, CD8/Treg ratio, and cancer stem cells are correlated with lymph node metastasis in patients with early breast cancer. Breast Cancer., 2020, 27(5): 837-849

[38] Wan Y, Zhang C, Xu Y, et al.. Hyperfunction of CD4 CD25 regulatory T cells in de novo acute myeloid leukemia. BMC Cancer., 2020, 20(1): 472

[39] Shenghui Z, Yixiang H, Jianbo W, et al.. Elevated frequencies of CD4(+) CD25(+) CD127lo regulatory T cells is associated to poor prognosis in patients with acute myeloid leukemia. Int J Cancer., 2011, 129(61373-1381

[40] Dehghani M, Kalani M, Golmoghaddam H, et al.. Aberrant peripheral blood CD4(+) CD25(+) FOXP3(+) regulatory T cells/T helper-17 number is associated with the outcome of patients with lymphoma. Cancer Immunol Immunother., 2020, 69(9): 1917-1928

[41] Wang M, Zhang C, Tian T, et al.. Increased Regulatory T Cells in Peripheral Blood of Acute Myeloid Leukemia Patients Rely on Tumor Necrosis Factor (TNF)-alpha-TNF Receptor-2 Pathway. Front Immunol., 2018, 9: 1274

[42] Khelfa M, Leclerc M, Kerbrat S, et al.. Divergent CD4(+) T-cell profiles are associated with anti-HLA alloimmunization status in platelet-transfused AML patients. Front Immunol., 2023, 14: 1165973

[43] Ustun C, Miller JS, Munn DH, et al.. Regulatory T cells in acute myelogenous leukemia: is it time for immunomodulation?. Blood., 2011, 118(19): 5084-5095

[44] Sakaguchi S, Ono M, Setoguchi R, et al.. Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol Rev., 2006, 212: 8-27

[45] Shevach EM, DiPaolo RA, Andersson J, et al.. The lifestyle of naturally occurring CD4+ CD25+ Foxp3+ regulatory T cells. Immunol Rev., 2006, 212: 60-73

[46] Qian F, Arner BE, Kelly KM, et al.. Interleukin-4 treatment reduces leukemia burden in acute myeloid leukemia. FASEB J., 2022, 36(5 e22328

[47] Uhl FM, Chen S, O'Sullivan D, et al. Metabolic reprogramming of donor T cells enhances graft-versus-leukemia effects in mice and humans. Sci Transl Med. 2020;12(567):eabb8969.

[48] Tuyt LM, Dokter WH, Esselink MT, et al.. Divergent effects of IL-10 and IL-4 on the proliferation and growth factor secretion by acute myeloblastic leukemic cells. Eur Cytokine Netw., 1995, 6(4231-235

[49] Pena-Martinez P, Eriksson M, Ramakrishnan R, et al.. Interleukin 4 induces apoptosis of acute myeloid leukemia cells in a Stat6-dependent manner. Leukemia., 2018, 32(3): 588-596

[50] Finch ER, Tukaramrao DB, Goodfield LL, et al.. Activation of PPARgamma by endogenous prostaglandin J(2) mediates the antileukemic effect of selenium in murine leukemia. Blood., 2017, 129(13): 1802-1810

[51] Wang Y, Sun X, Yuan S, et al.. Interleukin-1beta inhibits normal hematopoietic expansion and promotes acute myeloid leukemia progression via the bone marrow niche. Cytotherapy., 2020, 22(3): 127-134

[52] Barreyro L, Will B, Bartholdy B, et al.. Overexpression of IL-1 receptor accessory protein in stem and progenitor cells and outcome correlation in AML and MDS. Blood., 2012, 120(6): 1290-1298

[53] Zhang Y, Guo H, Zhang Z, et al.. IL-6 promotes chemoresistance via upregulating CD36 mediated fatty acids uptake in acute myeloid leukemia. Exp Cell Res., 2022, 415(1 113112

[54] Sanchez-Correa B, Bergua JM, Campos C, et al.. Cytokine profiles in acute myeloid leukemia patients at diagnosis: survival is inversely correlated with IL-6 and directly correlated with IL-10 levels. Cytokine., 2013, 61(3): 885-891

[55] Lameris R, Ruben JM, Iglesias-Guimarais V, et al.. A bispecific T cell engager recruits both type 1 NKT and Vgamma9Vdelta2-T cells for the treatment of CD1d-expressing hematological malignancies. Cell Rep Med., 2023, 4(3 100961

[56] Bae EA, Seo H, Kim IK, et al.. Roles of NKT cells in cancer immunotherapy. Arch Pharm Res., 2019, 42(7): 543-548

[57] Herr W, Eichinger Y, Beshay J, et al.. HLA-DPB1 mismatch alleles represent powerful leukemia rejection antigens in CD4 T-cell immunotherapy after allogeneic stem-cell transplantation. Leukemia., 2017, 31(2): 434-445

[58] Matsushita M, Yamazaki R, Ikeda H, et al.. Possible involvement of allogeneic antigens recognised by donor-derived CD4 cytotoxic T cells in selective GVL effects after stem cell transplantation of patients with haematological malignancy. Br J Haematol., 2006, 132(1): 56-65

[59] Kronenberg M, Engel I. NKT cells in the antitumor response: the beta version?. J Clin Invest., 2024, 134(4 e177663

[60] Singh AK, Tripathi P, Cardell SL. Type II NKT Cells: An Elusive Population With Immunoregulatory Properties. Front Immunol., 2018, 9: 1969

[61] Kinjo Y, Takatsuka S, Kitano N, et al.. Functions of CD1d-Restricted Invariant Natural Killer T Cells in Antimicrobial Immunity and Potential Applications for Infection Control. Front Immunol., 2018, 9: 1266

[62] Rossjohn J, Pellicci DG, Patel O, et al.. Recognition of CD1d-restricted antigens by natural killer T cells. Nat Rev Immunol., 2012, 12(12): 845-857

[63] Nelson A, Lukacs JD, Johnston B. The Current Landscape of NKT Cell Immunotherapy and the Hills Ahead. Cancers (Basel)., 2021, 13(205174

[64] Terabe M, Berzofsky JA. Tissue-Specific Roles of NKT Cells in Tumor Immunity. Front Immunol., 2018, 9: 1838

[65] Robertson FC, Berzofsky JA, Terabe M. NKT cell networks in the regulation of tumor immunity. Front Immunol., 2014, 5: 543

[66] Boeck CL, Amberger DC, Doraneh-Gard F, et al.. Significance of Frequencies, Compositions, and/or Antileukemic Activity of (DC-stimulated) Invariant NKT, NK and CIK Cells on the Outcome of Patients With AML. ALL and CLL. J Immunother., 2017, 40(6224-248

[67] Najera CAE, Cervantes LA, Retiguin FP, et al.. Low number of invariant NKT cells is associated with poor survival in acute myeloid leukemia. J Cancer Res Clin Oncol., 2012, 138(81427-1432

[68] Stavrou V, Fultang L, Booth S, et al.. Invariant NKT cells metabolically adapt to the acute myeloid leukaemia environment. Cancer Immunol Immunother., 2023, 72(3): 543-560

[69] Schmid H, Schneidawind C, Jahnke S, et al.. Culture-Expanded Human Invariant Natural Killer T Cells Suppress T-Cell Alloreactivity and Eradicate Leukemia. Front Immunol., 2018, 9: 1817

[70] Rao A, Agrawal A, Borthakur G, et al.. Gamma delta T cells in acute myeloid leukemia: biology and emerging therapeutic strategies. J Immunother Cancer., 2024, 12(2 e007981

[71] Pathak VK, Singh I, Sharma B, et al.. Unveiling the role of NK cells, NKT-like cells, and gammadelta cells in pathogenesis of type 1 reactions in leprosy. Heliyon., 2024, 10(3 e25254

[72] Richter J, Neparidze N, Zhang L, et al.. Clinical regressions and broad immune activation following combination therapy targeting human NKT cells in myeloma. Blood., 2013, 121(3): 423-430

[73] Terabe M, Matsui S, Park JM, et al.. Transforming growth factor-beta production and myeloid cells are an effector mechanism through which CD1d-restricted T cells block cytotoxic T lymphocyte-mediated tumor immunosurveillance: abrogation prevents tumor recurrence. J Exp Med., 2003, 198(111741-1752

[74] Sudul P, Piatkowska-Jakubas B, Pawlinski L, et al.. The Complexities of Diagnosis with Co-Existing Gaucher Disease and Hemato-Oncology-A Case Report and Review of the Literature. J Clin Med., 2023, 12(17): 5518

[75] Jamal E, Azmy E, Ayed M, et al.. Clinical Impact of Percentage of Natural Killer Cells and Natural Killer-Like T Cell Population in Acute Myeloid Leukemia. J Hematol., 2020, 9(362-70

[76] Liang S, Dong T, Yue K, et al.. Identification of the immunosuppressive effect of gammadelta T cells correlated to bone morphogenetic protein 2 in acute myeloid leukemia. Front Immunol., 2022, 13: 1009709

[77] Ganesan R, Chennupati V, Ramachandran B, et al.. Selective recruitment of gammadelta T cells by a bispecific antibody for the treatment of acute myeloid leukemia. Leukemia., 2021, 35(8): 2274-2284

[78] Van Acker HH, Anguille S, De Reu H, et al.. Interleukin-15-Cultured Dendritic Cells Enhance Anti-Tumor Gamma Delta T Cell Functions through IL-15 Secretion. Front Immunol., 2018, 9: 658

[79] Branella GM, Lee JY, Okalova J, et al.. Ligand-based targeting of c-kit using engineered gammadelta T cells as a strategy for treating acute myeloid leukemia. Front Immunol., 2023, 14: 1294555

[80] Kent A, Crump LS, Davila E. Beyond alphabeta T cells: NK, iNKT, and gammadeltaT cell biology in leukemic patients and potential for off-the-shelf adoptive cell therapies for AML. Front Immunol., 2023, 14: 1202950

[81] Peng Q, Huang R, Wang H, et al.. Immune characteristics and prognostic implications of mucosal-associated invariant T cells in acute myeloid leukemia. Cancer Immunol Immunother., 2023, 72(124399-4414

[82] Ioannidis M, Cerundolo V, Salio M. The Immune Modulating Properties of Mucosal-Associated Invariant T Cells. Front Immunol., 2020, 11: 1556

[83] Yigit M, Basoglu OF, Unutmaz D. Mucosal-associated invariant T cells in cancer: dual roles, complex interactions and therapeutic potential. Front Immunol., 2024, 15: 1369236

[84] Won EJ, Ju JK, Cho YN, et al.. Clinical relevance of circulating mucosal-associated invariant T cell levels and their anti-cancer activity in patients with mucosal-associated cancer. Oncotarget., 2016, 7(4676274-76290

[85] Treiner E. Mucosal-associated invariant T cells in hematological malignancies: Current knowledge, pending questions. Front Immunol., 2023, 14: 1160943

[86] Comont T, Nicolau-Travers ML, Bertoli S, et al.. MAIT cells numbers and frequencies in patients with acute myeloid leukemia at diagnosis: association with cytogenetic profile and gene mutations. Cancer Immunol Immunother., 2022, 71(4875-887

[87] Tien FM, Yao CY, Tsai XC, et al.. Dysregulated immune and metabolic pathways are associated with poor survival in adult acute myeloid leukemia with CEBPA bZIP in-frame mutations. Blood Cancer J., 2024, 14(115

[88] Miliotou AN, Papadopoulou LC. CAR T-cell Therapy: A New Era in Cancer Immunotherapy. Curr Pharm Biotechnol., 2018, 19(15-18

[89] He X, Feng Z, Ma J, et al.. Bispecific and split CAR T cells targeting CD13 and TIM3 eradicate acute myeloid leukemia. Blood., 2020, 135(10): 713-723

[90] Leick MB, Silva H, Scarfo I, et al.. Non-cleavable hinge enhances avidity and expansion of CAR-T cells for acute myeloid leukemia. Cancer Cell., 2022, 40(5): 494-508.e495

[91] Hu Y, Zhou Y, Zhang M, et al.. Genetically modified CD7-targeting allogeneic CAR-T cell therapy with enhanced efficacy for relapsed/refractory CD7-positive hematological malignancies: a phase I clinical study. Cell Res., 2022, 32(11): 995-1007

[92] Atar D, Ruoff L, Mast AS, et al.. Rational combinatorial targeting by adapter CAR-T-cells (AdCAR-T) prevents antigen escape in acute myeloid leukemia. Leukemia., 2024, 38(10): 2183-2195

[93] Leigh RS, Kaynak BL, Ruskoaho H, et al.. Development and comparison of single FLT3-inhibitors to dual FLT3/TAF1-inhibitors as an anti-leukemic approach. PLoS One., 2025, 20(3 e0320443

[94] Yao M, Yan W, Wang Y, et al.. IHCH9033, a novel class I HDAC inhibitor, synergizes with FLT3 inhibitor and rescues quizartinib resistance in FLT3-ITD AML via enhancing DNA damage response. Exp Hematol Oncol., 2025, 14(1): 15

[95] DiNardo CD, Wei AH. How I treat acute myeloid leukemia in the era of new drugs. Blood., 2020, 135(285-96

[96] Fiorenza S, Turtle CJ. CAR-T Cell Therapy for Acute Myeloid Leukemia: Preclinical Rationale, Current Clinical Progress, and Barriers to Success. BioDrugs., 2021, 35(3): 281-302

[97] Sanchez MD, Tirado N, Mensurado S, et al.. Generation and proof-of-concept for allogeneic CD123 CAR-Delta One T (DOT) cells in acute myeloid leukemia. J Immunother Cancer., 2022, 10(9 e005400

[98] Willier S, Rothamel P, Hastreiter M, et al.. CLEC12A and CD33 coexpression as a preferential target for pediatric AML combinatorial immunotherapy. Blood., 2021, 137(8): 1037-1049

[99] Wang H, Feng S, Zhu Y, et al.. The tandem CD33-CLL1 CAR-T as an approach to treat acute myeloid leukemia. Blood Transfus., 2025, 23(4): 338-347

[100] Wang QJ, Yu Z, Hanada KI et al. Preclinical Evaluation of Chimeric Antigen Receptors Targeting CD70-Expressing Cancers. Clin Cancer Res. 2017;23(9):2267–2276.

[101] Miao X, Shuai Y, Han Y, et al.. Case report: Donor-derived CLL-1 chimeric antigen receptor T-cell therapy for relapsed/refractory acute myeloid leukemia bridging to allogeneic hematopoietic stem cell transplantation after remission. Front Immunol., 2024, 15: 1389227

[102] Jin X, Zhang M, Sun R, et al.. First-in-human phase I study of CLL-1 CAR-T cells in adults with relapsed/refractory acute myeloid leukemia. J Hematol Oncol., 2022, 15(1): 88

[103] Jin X, Xie D, Sun R, et al.. CAR-T cells dual-target CD123 and NKG2DLs to eradicate AML cells and selectively target immunosuppressive cells. Oncoimmunology., 2023, 12(12248826

[104] Stefik P, Annusova A, Lakatos B, et al. Targeting acute myeloid leukemia cells by CD33 receptor-specific MoS(2)-based nanoconjugates. Biomed Mater. 2021;16(5).

[105] Villamor N, Zarco MA, Rozman M, et al.. Acute myeloblastic leukemia with minimal myeloid differentiation: phenotypical and ultrastructural characteristics. Leukemia., 1998, 12(71071-1075

[106] Daver N, Alotaibi AS, Bucklein V, et al.. T-cell-based immunotherapy of acute myeloid leukemia: current concepts and future developments. Leukemia., 2021, 35(71843-1863

[107] Haen SP, Loffler MW, Rammensee HG, et al.. Towards new horizons: characterization, classification and implications of the tumour antigenic repertoire. Nat Rev Clin Oncol., 2020, 17(10): 595-610

[108] Abbott RC, Cross RS, Jenkins MR. Finding the Keys to the CAR: Identifying Novel Target Antigens for T Cell Redirection Immunotherapies. Int J Mol Sci., 2020, 21(2): 515

[109] Minati R, Perreault C, Thibault P. A Roadmap Toward the Definition of Actionable Tumor-Specific Antigens. Front Immunol., 2020, 11 583287

[110] Apavaloaei A, Perreault C. Immunotargeting of a recurrent AML-specific neoantigen. Nat Cancer., 2023, 4(101403-1405

[111] Giannakopoulou E, Lehander M, Virding CS, et al.. A T cell receptor targeting a recurrent driver mutation in FLT3 mediates elimination of primary human acute myeloid leukemia in vivo. Nat Cancer., 2023, 4(10): 1474-1490

[112] Reynisson B, Alvarez B, Paul S, et al. NetMHCpan-4.1 and NetMHCIIpan-4.0: improved predictions of MHC antigen presentation by concurrent motif deconvolution and integration of MS MHC eluted ligand data. Nucleic Acids Res. 2020;48(W1):W449–W454.

[113] Mei S, Li F, Leier A, et al.. A comprehensive review and performance evaluation of bioinformatics tools for HLA class I peptide-binding prediction. Brief Bioinform., 2020, 21(4): 1119-1135

[114] Springer I, Besser H, Tickotsky-Moskovitz N, et al.. Prediction of Specific TCR-Peptide Binding From Large Dictionaries of TCR-Peptide Pairs. Front Immunol., 2020, 11: 1803

[115] Tan X, Li D, Huang P, et al. dbPepNeo: a manually curated database for human tumor neoantigen peptides. Database (Oxford). 2020;2020:baaa004.

[116] Liu R, Jiang W, Mellins ED. Yeast display of MHC-II enables rapid identification of peptide ligands from protein antigens (RIPPA). Cell Mol Immunol., 2021, 18(8): 1847-1860

[117] van Balen P, Jedema I, van Loenen MM, et al.. HA-1H T-Cell Receptor Gene Transfer to Redirect Virus-Specific T Cells for Treatment of Hematological Malignancies After Allogeneic Stem Cell Transplantation: A Phase 1 Clinical Study. Front Immunol., 2020, 11: 1804

[118] Tawara I, Kageyama S, Miyahara Y, et al.. Safety and persistence of WT1-specific T-cell receptor gene-transduced lymphocytes in patients with AML and MDS. Blood., 2017, 130(181985-1994

[119] Damiani D, Tiribelli M. Checkpoint Inhibitors in Acute Myeloid Leukemia. Biomedicines., 2023, 11(61724

[120] Tettamanti S, Pievani A, Biondi A, et al.. Catch me if you can: how AML and its niche escape immunotherapy. Leukemia., 2022, 36(113-22

[121] Das S, Johnson DB. Immune-related adverse events and anti-tumor efficacy of immune checkpoint inhibitors. J Immunother Cancer., 2019, 7(1): 306

[122] Daver NG, Maiti A, Kadia TM, et al.. TP53-Mutated Myelodysplastic Syndrome and Acute Myeloid Leukemia: Biology, Current Therapy, and Future Directions. Cancer Discov., 2022, 12(112516-2529

[123] Liao D, Wang M, Liao Y, et al.. A Review of Efficacy and Safety of Checkpoint Inhibitor for the Treatment of Acute Myeloid Leukemia. Front Pharmacol., 2019, 10: 609

[124] Aru B, Pehlivanoglu C, Dal Z, et al.. A potential area of use for immune checkpoint inhibitors: Targeting bone marrow microenvironment in acute myeloid leukemia. Front Immunol., 2023, 14: 1108200

[125] Stahl M, Goldberg AD. Immune Checkpoint Inhibitors in Acute Myeloid Leukemia: Novel Combinations and Therapeutic Targets. Curr Oncol Rep., 2019, 21(4): 37

[126] Gomez-Llobell M, Peleteiro RA, Climent MJ, et al.. Immune Checkpoint Inhibitors in Acute Myeloid Leukemia: A Meta-Analysis. Front Oncol., 2022, 12 882531

[127] Williams P, Basu S, Garcia-Manero G, et al.. The distribution of T-cell subsets and the expression of immune checkpoint receptors and ligands in patients with newly diagnosed and relapsed acute myeloid leukemia. Cancer., 2019, 125(91470-1481

[128] Chen C, Liang C, Wang S, et al.. Expression patterns of immune checkpoints in acute myeloid leukemia. J Hematol Oncol., 2020, 13(128

[129] Abaza Y, Zeidan AM. Immune Checkpoint Inhibition in Acute Myeloid Leukemia and Myelodysplastic Syndromes. Cells., 2022, 11(142249

[130] Kim ST, Sheshadri A, Shannon V, et al.. Distinct Immunophenotypes of T Cells in Bronchoalveolar Lavage Fluid From Leukemia Patients With Immune Checkpoint Inhibitors-Related Pulmonary Complications. Front Immunol., 2020, 11 590494

[131] Sheshadri A, Goizueta AA, Shannon VR, et al.. Pneumonitis after immune checkpoint inhibitor therapies in patients with acute myeloid leukemia: A retrospective cohort study. Cancer., 2022, 128(142736-2745

[132] Gupta D, Bhattacharjee O, Mandal D, et al.. CRISPR-Cas9 system: A new-fangled dawn in gene editing. Life Sci., 2019, 232 116636

[133] Bexte T, Albinger N, Al AA, et al.. CRISPR/Cas9 editing of NKG2A improves the efficacy of primary CD33-directed chimeric antigen receptor natural killer cells. Nat Commun., 2024, 15(1): 8439

[134] Neldeborg S, Soerensen JF, Moller CT, et al.. Dual intron-targeted CRISPR-Cas9-mediated disruption of the AML RUNX1-RUNX1T1 fusion gene effectively inhibits proliferation and decreases tumor volume in vitro and in vivo. Leukemia., 2023, 37(91792-1801

[135] Thakur A, Huang M, Lum LG. Bispecific antibody based therapeutics: Strengths and challenges. Blood Rev., 2018, 32(4): 339-347

[136] Kubicka E, Lum LG, Huang M, et al.. Bispecific antibody-targeted T-cell therapy for acute myeloid leukemia. Front Immunol., 2022, 13 899468

[137] Yeung YA, Krishnamoorthy V, Dettling D, et al.. An Optimized Full-Length FLT3/CD3 Bispecific Antibody Demonstrates Potent Anti-leukemia Activity and Reversible Hematological Toxicity. Mol Ther., 2020, 28(3): 889-900

[138] Imai Y. Novel treatment strategies for hematological malignancies in the immunotherapy era. Int J Hematol., 2024, 120(1): 3-5

[139] Merino A, Maakaron J, Bachanova V. Advances in NK cell therapy for hematologic malignancies: NK source, persistence and tumor targeting. Blood Rev., 2023, 60 101073

[140] Saito S, Nakazawa Y. CAR-T cell therapy in AML: recent progress and future perspectives. Int J Hematol., 2024, 120(4): 455-466

[141] Panuciak K, Margas M, Makowska K, et al.. Insights into Modern Therapeutic Approaches in Pediatric Acute Leukemias. Cells., 2022, 11(1): 139

[142] Ma C, Chen P, Du J, et al.. Adoptive transfer of CMV-specific TCR-T cells for the treatment of CMV infection after haploidentical hematopoietic stem cell transplantation. J Immunother Cancer., 2024, 12(1 e007735

[143] Durbin SM, Zubiri L, Perlman K, et al.. Late-Onset Immune-Related Adverse Events After Immune Checkpoint Inhibitor Therapy. JAMA Netw Open., 2025, 8(3 e252668

[144] Perkin P, Sekmek S, Bayram D, et al. Pembrolizumab associated immune thrombocytopenia. J Chemother. 2025:1–5.

[145] Shen H, McHale CM, Smith MT, et al.. Functional genomic screening approaches in mechanistic toxicology and potential future applications of CRISPR-Cas9. Mutat Res Rev Mutat Res., 2015, 764: 31-42

[146] Patel S, Jenkins E, Kusurkar RP, et al.. Targeting BARD1 suppresses a Myc-dependent transcriptional program and tumor growth in pancreatic ductal adenocarcinoma. Neoplasia., 2025, 63 101152

[147] Man JC, Cheng J, Zhao L. Effect of Knocking Out HOXA5 Gene by CRISPR-Cas9-Mediated Gene Editing Technique on Proliferation of Acute Myeloid Leukemia Cells. Zhongguo Shi Yan Xue Ye Xue Za Zhi (Chinese)., 2024, 32(152-56

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