T-cell-based immunotherapy of acute myeloid leukemia: current concepts and future developments

Abstract

Acute myeloid leukemia (AML) is a heterogeneous disease linked to a broad spectrum of molecular alterations, and as such, long-term disease control requires multiple therapeutic approaches. Driven largely by an improved understanding and targeting of these molecular aberrations, AML treatment has rapidly evolved over the last 3–5 years. The stellar successes of immunotherapies that harness the power of T cells to treat solid tumors and an improved understanding of the immune systems of patients with hematologic malignancies have led to major efforts to develop immunotherapies for the treatment of patients with AML. Several immunotherapies that harness T cells against AML are in various stages of preclinical and clinical development. These include bispecific and dual antigen receptor-targeting antibodies (targeted to CD33, CD123, CLL-1, and others), chimeric antigen receptor (CAR) T-cell therapies, and T-cell immune checkpoint inhibitors (including those targeting PD-1, PD-L1, CTLA-4, and newer targets such as TIM3 and STING). The current and future directions of these T-cell-based immunotherapies in the treatment landscape of AML are discussed in this review.

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85. 85.

    Toffalori C, Zito L, Gambacorta V, Riba M, Oliveira G, Bucci G, et al. Immune signature drives leukemia escape and relapse after hematopoietic cell transplantation. Nat Med. 2019;25:603-11.

    Not in our library10.1038/s41591-019-0400-z

86. 86.

    Greiner J, Ono Y, Hofmann S, Schmitt A, Mehring E, Götz M, et al. Mutated regions of nucleophosmin 1 elicit both CD4+ and CD8+ T-cell responses in patients with acute myeloid leukemia. Blood. 2012;120:1282-9.

    Not in our library10.1182/blood2011-11-394395

87. 87.

    van der Lee DI, Reijmers R, Honders MW, Hagedoorn RS, de Jong RCM, Kester MGD, et al. Mutated nucleophosmin 1 as immunotherapy target in acute myeloid leukemia. J Clin Invest. 2019;129:774-85.

    Not in our library10.1172/jci97482

88. 88.

    Schumacher T, Bunse L, Pusch S, Sahm F, Wiestler B, Quandt J, et al. A vaccine targeting mutant IDH1 induces antitumour immunity. Nature. 2014;512:324-7.

    Not in our library10.1038/nature13387

89. 89.

    Graf C, Heidel F, Tenzer S, Radsak MP, Solem FK, Britten CM, et al. A neoepitope generated by an FLT3 internal tandem duplication (FLT3-ITD) is recognized by leukemia-reactive autologous CD8+ T cells. Blood. 2007;109:2985-8.

    Not in our library10.1182/blood-2006-07-0322839

90. 90.

    Gambacorti-Passerini CF, Grignani F, Arienti F, Pandolfi PP, Pelicci PG, Parmiani G. Human CD4 lymphocytes specifically recognize a peptide representing the fusion region of the hybrid protein pml/RAR alpha present in acute promyelocytic leukemia cells. Blood. 1993;81:1369-75.

    Not in our library10.1182/blood.v81.5.1369.1369

91. 91.

    Makita M, Azuma T, Hamaguchi, Niiya H, Kojima K, Fujita S, et al. Leukemia-associated fusion proteins, dek-can and bcr-abl, represent immunogenic HLA-DR-restricted epitopes recognized by fusion peptide-specific CD4+ T lymphocytes. Leukemia. 2002;16:2400-7.

    Not in our library10.1038/sj.leu.2402742

92. 92.

    Kovtun Y, Jones GE, Adams S, Harvey L, Audette CA, Wilhelm A, et al. A CD123-targeting antibody-drug conjugate, IMGN632, designed to eradicate AML while sparing normal bone marrow cells. Blood Adv. 2018;2:848-58.

    Not in our library10.1182/bloodadvances.2018017517

93. 93.

    Ehninger A, Kramer M, Röllig C, Thiede C, Bornhäuser M, von Bonin M, et al. Distribution and levels of cell surface expression of CD33 and CD123 in acute myeloid leukemia. Blood Cancer J. 2014;4:e218.

    Not in our library10.1038/bcj.2014.39

94. 94.

    Escribano L, Ocqueteau M, Almeida J, Orfao A, San Miguel JF. Expression of the c-kit (CD117) molecule in normal and malignant hematopoiesis. Leuk Lymphoma. 1998;30:459-66.

    Not in our library10.3109/10428199809057558

95. 95.

    Scolnik MP, Morilla R, de E, de Bracco MM, Catovsky D, Matutes E. CD34 and CD117 are overexpressed in AML and may be valuable to detect minimal residual disease. Leuk Res. 2002;26:615-9.

    Not in our library10.1016/s0145-2126(01)00182-5

96. 96.

    Kandeel EZ, El Sayed G, Elsharkawy N, Negm Eldin D, Nassar HR, Ibrahiem D, et al. Impact of FLT3 Receptor (CD135) detection by flow cytometry on clinical outcome of adult acute myeloid leukemia patients. Clin Lymphoma Myeloma Leukemia. 2018;18:541-7.

    Not in our library10.1016/j.clml.2018.05.014

97. 97.

    Lynn RC, Poussin M, Kalota A, Feng Y, Low PS, Dimitrov DS, et al. Targeting of folate receptor β on acute myeloid leukemia blasts with chimeric antigen receptor-expressing T cells. Blood. 2015;125:3466-76.

    Not in our library10.1182/blood-2014-11-612721

98. 98.

    Mitchell K, Barreyro L, Todorova TI, Taylor SJ, Antony-Debré I, Narayanagari S-R, et al. IL1RAP potentiates multiple oncogenic signaling pathways in AML. J Exp Med. 2018;215:1709-27.

    Not in our library10.1084/jem.20180147

99. 99.

    Askmyr M, Ågerstam H, Hansen N, Gordon S, Arvanitakis A, Rissler M, et al. Selective killing of candidate AML stem cells by antibody targeting of IL1RAP. Blood. 2013;121:3709-13.

    Not in our library10.1182/blood-2012-09-458935

100. 100.

     Sergeeva A, Alatrash G, He H, Ruisaard K, Lu S, Wygant J, et al. An anti-PR1/HLA-A2 T-cell receptor-like antibody mediates complement-dependent cytotoxicity against acute myeloid leukemia progenitor cells. Blood. 2011;117:4262-72.

     Not in our library10.1182/blood-2010-07-299248

101. 101.

     Alatrash G, Molldrem JJ, Qazilbash MH. Targeting PR1 in myeloid leukemia. Oncotarget. 2017;9:4280-1.

     Not in our library10.18632/oncotarget.23403

102. 102.

     Muroi K, Suda T, Nojiri H, Ema H, Amemiya Y, Miura Y, et al. Reactivity profiles of leukemic myeloblasts with monoclonal antibodies directed to sialosyl-Le(x) and other lacto-series type 2 chain antigens: absence of reactivity with normal hematopoietic progenitor cells. Blood. 1992;79:713-9.

     Not in our library10.1182/blood.v79.3.713.713

103. 103.

     Zhang S, Zhang HS, Cordon-Cardo C, Reuter VE, Singhal AK, Lloyd KO, et al. Selection of tumor antigens as targets for immune attack using immunohistochemistry: II. Blood group-related antigens. Int J Cancer. 1997;73:50–6. 10.1002/(SICI)1097-0215(19970926)73:1<50::AID-IJC9>3.0.CO;2-0.

     Not in our library10.1002/(sici)1097-0215(19970926)73:1<50::aid-ijc9>3.0.co;2-0

104. 104.

     Stroopinsky D, Rosenblatt J, Ito K, Mills H, Yin L, Rajabi H, et al. MUC1 is a potential target for the treatment of acute myeloid leukemia stem cells. Cancer Res. 2013;73:5569-79.

     Not in our library10.1158/0008-5472.can-13-0677

105. 105.

     Stroopinsky D, Rajabi H, Nahas M, Rosenblatt J, Rahimian M, Pyzer A, et al. MUC1-C drives myeloid leukaemogenesis and resistance to treatment by a survivin-mediated mechanism. J Cell Mol Med. 2018;22:3887-98.

     Not in our library10.1111/jcmm.13662

106. 106.

     Legras S, Günthert U, Stauder R, Curt F, Oliferenko S, Kluin-Nelemans HC, et al. A strong expression of CD44-6v correlates with shorter survival of patients with acute myeloid leukemia. Blood. 1998;91:3401-13.

     Not in our library10.1182/blood.v91.9.3.3401

107. 107.

     Neu S, Geiselhart A, Sproll M, Hahn D, Kuçi S, Niethammer D, et al. Expression of CD44 isoforms by highly enriched CD34-positive cells in cord blood, bone marrow and leukaphereses. Bone Marrow Transplant. 1997;20:593-8.

     Not in our library10.1038/sj.bmt.1700940

108. 108.

     Casucci M, Nicolis di Robilant B, Falcone L, Camisa B, Norelli M, Genovese P, et al. CD44v6-targeted T cells mediate potent antitumor effects against acute myeloid leukemia and multiple myeloma. Blood. 2013;122:3461-72.

     Not in our library10.1182/blood-2013-04-493361

109. 109.

     Hosen N, Park CY, Tatsumi N, Oji Y, Sugiyama H, Gramatzki M, et al. CD96 is a leukemic stem cell-specific marker in human acute myeloid leukemia. Proc Natl Acad Sci USA. 2007;104:11008-13.

     Not in our library10.1073/pnas.0704271104

110. 110.

     Kikushige Y, Shima T, Takayanagi S-I, Urata S, Miyamoto T, Iwasaki H, et al. TIM-3 is a promising target to selectively kill acute myeloid leukemia stem cells. Cell Stem Cell. 2010;7:708-17.

     Not in our library10.1016/j.stem.2010.11.014

111. 111.

     Riether C, Schürch CM, Bührer ED, Hinterbrandner M, Huguenin A-L, Hoepner S, et al. CD70/CD27 signaling promotes blast stemness and is a viable therapeutic target in acute myeloid leukemia. J Exp Med. 2016;214:359-80.

     Not in our library10.1084/jem.20152008

112. 112.

     Rosenfeld C, Cheever MA, Gaiger A. WT1 in acute leukemia, chronic myelogenous leukemia and myelodysplastic syndrome: Therapeutic potential of WT1 targeted therapies. Leukemia. 2003;17:1301-12.

     Not in our library10.1038/sj.leu.2402988

113. 113.

     Qin Y, Zhu H, Jiang B, Li J, Lu X, Li L, et al. Expression patterns of WT1 and PRAME in acute myeloid leukemia patients and their usefulness for monitoring minimal residual disease. Leuk Res. 2009;33:384-90.

     Not in our library10.1016/j.leukres.2008.08.026

114. 114.

     Ding K, Wang X-m, Fu R, Ruan E-b, Liu H, Shao Z-h. PRAME gene expression in acute leukemia and its clinical significance. Cancer Biol Med. 2012;9:73–6. 10.3969/j.issn.2095-3941.2012.01.013.

     Not in our library10.3969/j.issn.2095-3941.2012.01.013

115. 115.

     Rezvani K, Yong ASM, Tawab A, Jafarpour B, Eniafe R, Mielke S, et al. Ex vivo characterization of polyclonal memory CD8+ T-cell responses to PRAME-specific peptides in patients with acute lymphoblastic leukemia and acute and chronic myeloid leukemia. Blood. 2009;113:2245-55.

     Not in our library10.1182/blood-2008-03-144071

116. 116.

     Casalegno-Garduño R, Meier C, Mani J, Borchert K, Hilgendorf I, Gross Y, et al. Expression of RHAMM and wt1 as well as t cell responses to these antigens before and after allogeneic stem cell transplantation in patients with leukemia. Blood. 2011;118:4315.

     Not in our library10.1182/blood.v118.21.4315.4315

117. 117.

     Greiner J, Schmitt A, Giannopoulos K, Rojewski MT, Götz M, Funk I, et al. High-dose RHAMM-R3 peptide vaccination for patients with acute myeloid leukemia, myelodysplastic syndrome and multiple myeloma. Haematologica. 2010;95:1191-7.

     Not in our library10.3324/haematol.2009.014704

118. 118.

     Snauwaert S, Vanhee S, Goetgeluk G, Verstichel G, Van Caeneghem Y, Velghe I, et al. RHAMM/HMMR (CD168) is not an ideal target antigen for immunotherapy of acute myeloid leukemia. Haematologica. 2012;97:1539-47.

     Not in our library10.3324/haematol.2012.065581

119. 119.

     Andersen MH, Pedersen LØ, Capeller B, Bröcker E-B, Becker JC, thor Straten P. Spontaneous cytotoxic T-cell responses against survivin-derived MHC class I-restricted T-cell epitopes in situ as well as ex vivo in cancer patients. Cancer Res. 2001;61:5964-8.

     Not in our library

120. 120.

     Carter BZ, Qiu Y, Huang X, Diao L, Zhang N, Coombes KR, et al. Survivin is highly expressed in CD34+38– leukemic stem/progenitor cells and predicts poor clinical outcomes in AML. Blood. 2012;120:173-80.

     Not in our library10.1182/blood-2012-02-409888

121. 121.

     Xing Z, Conway EM, Kang C, Winoto A. Essential role of survivin, an inhibitor of apoptosis protein, in T cell development, maturation, and homeostasis. J Exp Med. 2003;199:69-80.

     Not in our library10.1084/jem.20031588

122. 122.

     Fukuda S, Hoggatt J, Singh P, Abe M, Speth JM, Hu P, et al. Survivin modulates genes with divergent molecular functions and regulates proliferation of hematopoietic stem cells through Evi-1. Leukemia. 2014;29:433-40.

     Not in our library10.1038/leu.2014.183

123. 123.

     Hiyama E, Hiyama K, Yokoyama T, Shay JW. Immunohistochemical detection of telomerase (hTERT) protein in human cancer tissues and a subset of cells in normal tissues. Neoplasia. 2001;3:17-26.

     Not in our library10.1038/sj.neo.7900134

124. 124.

     Bruedigam C, Bagger FO, Heidel FH, Kuhn CP, Guignes S, Song A, et al. Telomerase inhibition effectively targets mouse and human AML stem cells and delays relapse following chemotherapy. Cell Stem Cell. 2014;15:775-90.

     Not in our library10.1016/j.stem.2014.11.010

125. 125.

     Hartmann U, Brümmendorf TH, Balabanov S, Thiede C, Illme T, Schaich M. Telomere length and hTERT expression in patients with acute myeloid leukemia correlates with chromosomal abnormalities. Haematologica. 2005;90:307-16.

     Not in our library

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• CAR-T cell therapy for cancer: current challenges and future directions · 2025
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