Table 1.
Characteristics of AML target antigens proposed for CAR T-cell therapy: .
| AML Antigen | Common Alias(es) | Clinical Trial Status | Associated Effector Functions | Normal Cellular Expression Profile | AML Patient Prevalence with Antigen Expression (%) | % bulk cells OR % LSC Antigen Expression | CAR CombinationalStrategies | Reference(s) |
|---|---|---|---|---|---|---|---|---|
| CD123 | IL-3RA | Phase I/II Phase II/III (with CLL-1) |
Production and differentiation of HPCs into myeloid and lymphoid lineage-restricted cells | HPCs, monocytes, megakaryocytes, plasmacytoid dendritic cells, and B-lymphocytes | 45% - 95% (8) (9–11) | LSC: 95.3% (12) | CD33 CLL1 |
(13, 14) |
| CLL-1 | CLEC12A, DCAL-2, MICL, CD371 |
Phase I/II Phase II/III (with CD123) |
Cell adhesion, cell-cell signaling, glycoprotein turnover, inflammation, immune response; negative regulator of granulocyte and monocyte function | HSCs (2.5%), HPCs, myeloid progenitors, mature myelocytes (15) | 85% - 92% (16) | Bulk cells: 77.5% – 92% LSC: 45.1% (12) |
CD123 CD33 |
(17) |
| CD19 | B-lymphocyte surface antigen B4 | Phase II/III | B-cell differentiation | B- lymphocytes | 3.2% (AML, n = 527) with 66% (mixed-phenotype, n = 3) (18) |
Bulk cells: 5% - 34% (AML) (18) |
– | (18) |
| CD7 | TP41 | Phase I/II | T-cell/B-cell interaction during early lymphoid development, mature T-cell interactions | Thymocytes, NK cell precursors, T-lymphocytes | 30% (n = 20) (19) | Bulk cells: 95.6% (n = 1) (20) Blast: 45.1% (21) |
– | (19, 20) |
| CD33 | SIGLEC3 | Phase I/II | Negative regulator of cytokine production and monocyte activation | HPCs, myeloid progenitors, mature myelocytes | 85% - 90% (8) | LSC: 88.7% (12) | CD123 CLL1 |
(22) |
| CD38 | ADPRC1 | Phase I/II | Synthesis and hydrolyzes cyclic adenosine 5’-diphosphate-ribose (intracellular calcium ion mobilizer) | Myeloid progenitors, T-lymphocytes (activated), B-lymphocytes (activated), monocytes, NK cells | 37.3% (M1), 46.9% (M2), 5.1% (M3), 38.1 (M4), 54.6% (M5), 45.5% (M6) (n = 304) (23) | Bulk cells: 95% (n =6) (24) Blast: 83% (n=93) (25) Blast: 78% (n = 304) (23) |
– | (24, 26) |
| CD44v6 | HCAM, Pgp-1, HUTCH-1, LHR | Phase I/II | Cell-cell interactions, cell adhesion, migration; lymphocyte activation, recirculation & homing, hematopoiesis, metastasis | Monocytes | 64% (n = 25) (27) | Not Reported | – | (27, 28) |
| CD70 | TNFSF7 | Phase I/II | Proliferation of stimulated T-cells, enhance cytotoxic T-cell generation, T-cell activation | B- lymphocytes (activated), T-lymphocytes (activated) | 86% (n = 30) (5) | LSC: >75% (5) | – | (29, 30) |
| FLT3 | CD135, FLK2 | Phase I/II | Apoptosis, proliferation, and differentiation of hematopoietic stem cells in bone marrow | HPCs, GMPs, B-lymphocytes, Dendritic cells, NK cells | 70% - 100% (31) Mutated 27% (n = 854) (32) |
Bulk cells: 5% -10% (ITD mutation), 2% - 5% (TKD missense mutation) (33) | – | (34) |
| Siglec-6 | CD327, CD33L, OBBP1 | Phase I/II | Putative adhesion molecule mediates sialic-acid dependent binding to cells | Mast cells, granulocytes, syncytiotrophoblasts, cytotrophoblasts | 100% (n = 20 using biotinylated anti-Siglec-6 mAb) (35) | Bulk cells: 76.9% (35) | – | (35) |
| NKG2DL | CD314, KLR | Phase I/II | Activator of NK and T cells; Immune recognition of cellular stress | NK cells (mature), NKT (mature), γδ T lymphocytes (mature) | 75% - 80% (36, 37) | Bulk cells: 67% to 100% MICA/B and/or ULBP2-3 (36, 37) | – | (38, 39) |
| WT1 | WIT-2, WAGR, AWT1 | Phase I/II | Organ development, differentiation, proliferation, and apoptosis | Mesodermal tissues (HSCs, myoepithelial progenitors, renal podocytes, ovary and testis) | 88.3% (n = 60) (40) 70% - 90% (41) |
Not Reported | – | (42, 43) |
| Lewis Y | CD174, FUT3 | Phase I | Embryogenesis, tissue differentiation, tumor metastasis, inflammation, and bacterial adhesion | Granulocytes, synctiotrophoblasts | 52% (n = 29) (44) 46% (n = 52) (45) |
Not Reported | – | (46) |
| ADGRE2 | EMR2 | Phase I | Promotes cell-cell adhesion through interaction with chondroitin sulfate chains, promotes granulocyte chemotaxis, degranulation & adhesion | Monocytes, macrophages, Kupffer cells, granulocytes, neutrophils | 100% (n = 109) (47) 93% (n = 30) (5) |
Bulk cells: 87.8% (47) LSC: >75% (5) |
– | (48) |
| ILT3 | LILRB4, CD85k, LIR5 | Phase I | Inhibitor of MHC class 1 immune activation | Monocytes, Macrophages, Dendritic Cells | 100% (M5) (n = 17) (49) 97% (M4, n = 33), 100% (M5, n = 26) (50) |
Bulk cells: 99% (Monocytic AML) (49) Bulk cells: ~75% (M4), ~100% (M5) (50) |
– | (49) |
| B7-H3 | CD276 | N/A | May regulate T-cell mediated immune response | Trophoblasts | 27% (n =111) (51) | Bulk cells: 57.2% (n = 8, mean bone marrow) (52) | CD70 | (52–54) |
| FRβ | FBP | – | Folate receptor and transporter; DNA synthesis, methylation, and repair | Myeloid-lineage hematopoietic cells | 68% (n=78) (55) | Not Reported | – | (56, 57) |
| PR1 peptide | VLQELNVTV | – | HLA-A2 peptide from leukemia-associated proteinase 3 and neutrophil elastase presented to cytotoxic T cells | N/A | Elevated (n = 9) (58) | Not Reported | – | (59) |
| CD64 | Fc-gamma receptor 1 | – | Innate and adaptive immune response to Fc region of immunoglobulin gamma | Myeloid cells, monocytes, macrophages, endothelial cells (cytokine induction), Neurons (cytokine induction) | 46.8% (n = 64) (60) | Bulk cells: Variable (60) | – | (61) |
| CD116 | CD116/CD131 complex GM-CSF Receptor (mutated) |
– | Production, differentiation, and function of granulocytes and macrophages | GMPs, Granulocytes, Macrophages | CD116 overexpressed 63% - 78% (62) 83% (n=29) (63) |
Bulk cells: 1% - 98.1% (63) | – | (63) |
| c-KIT | SCFR, PBT, CD117 | – | Regulation of cell survival, proliferation, hematopoiesis, stem cell maintenance, gametogenesis, mast cell development, migration | Enhanced in granulocytes, melanocytes, inhibitory neurons, monocytes, breast glandular cells | 64.9% (n = 75) (64) 70%-100% (65) |
Bulk cells: 70% (65) | – | (65) |
| GRP78 | HSPA5, BIP | – | May facilitate viral attachment and entry to host cells | Upregulated during cellular stress | >50% (n = 14), overexpressed in TARGET, TCGA microarray data, & MILE study (66), | Not Reported | – | (66) |
| IL1RAP | IL1R3 | – | Component of interleukin 1 receptor complex which induces synthesis of acute phase and proinflammatory proteins during infection, tissue damage, or stress | Hepatocytes, placenta, monocytes, peripheral mononuclear cells | 79% (n = 29) (67) | Not Reported | – | (68) |
| TIM-3 | HAVCR2 | – | Regulates macrophage activation, inhibits Th1-mediated auto- and alloimmune responses, promotes immunological tolerance | T lymphocytes (mature), Treg cells, macrophages, NK cells, dendritic cells, mast cells | [Vast majority] (69) | Bulk cells: 87.3% LSC: 78.5% (12) |
CD13 | (70) |
| CD13 | ANPEP, Alanyl Aminopeptidase LAP1, PEPN, GP150, HAPN | – | Digestion of peptides, metabolisms of regulatory peptides, promote angiogenesis, tumor growth, metastasis | Enterocytes, hepatocytes, exocrine glandular cells, proximal tubule cells, prostate glandular cells, decidual cells | 44% (n = 12) (71) | Not Reported | TIM-3 | (72, 73) |
| CD93 | C1QR1 | – | Phagocytosis of apoptotic cells | Neutrophils, monocytes, plasmacytoid dendritic cells, myeloid dendritic cells, PBMCs | 56.7% (74) | Not Reported | – | (75) |
Summary of AML antigens currently under preclinical and clinical investigation by clinical trial status, associated effector function, normal cellular expression profile, AML patient prevalence of antigen expression, % bulk cells OR % LSC antigen expression (at diagnosis), and CAR combinational strategies. Please note that % of patient positivity may not necessarily reflect antigen expression levels.