Table 1 Introduction to the targets involved in the study of CAR-T/NK for AML
From: Biomarkers as targets for CAR-T/NK cell therapy in AML
Targets | Molecule type | Function | Current recruiting research | Distribution | References | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
Normal | Disease status | HSC | LSC | AML primitive cells | |||||||
CD33 (Siglec-3) | Sialic acid-binding immunoglobulin, adhesion molecule | Myeloid differentiation antigens with endocytic properties, sialic acid-dependent cell adhesion molecules | Phase I/II clinical trials on CAR-T in China and US Phase I clinical trials on CAR-NK in China and US Phase I clinical trials on CD33/CLL1 CAR-T in China A phase I clinical trial on CD33/CLL1 CAR-NK in China | Myeloid cells (including myeloid precursor cells), neutrophils, NK cells, B cells, hepatic Kupffer cells, and microglia in the central nervous system | Expressed in approximately 85–90% of AML patients and in nearly 90% of AML cells in patients, has greater expression in normal karyotype or NPM1-positive AML | Yes | Yes | Yes | |||
CD123 (IL3Rα) | Type I cytokine receptor | IL-3 receptor | A phase I clinical trial on CAR-NK in China Phase I/II clinical trials on CAR-T in China, US and Germany | Myeloid cells (including myeloid precursor cells), dendritic cells, endothelial cells, basophils, trachea, gastrointestinal tissue | Expressed abundantly on 78% of AML primary cells, LSC | Yes | Yes | Yes | |||
Siglec-6 | Sialic acid-binding immunoglobulin-like agglutinin 6 | Immunosuppressive molecules | A phase I/II clinical trial on CAR-T in China | B cells, mast cells, placenta | Usually expressed in leukemia patients, including 60% of AML primary cells and stem cells | No | Yes | Yes | [19] | ||
TIM3 (HAVCR2) | T-cell immunoglobulin and mucin structural domain 3, immunoglobulin superfamily | Immunomodulation through regulation of macrophage activity, inhibition of Th1 and Th17 effects and attenuation of TCR signaling; the synthesis of TIM3 to lessen the immune system's cytotoxic killing effect is one of the immunological escape strategies in AML | Preclinical trials: no current clinical trials using TIM3 CAR-T/NK | T cells, myeloid cells, NK cells, lung tissue | Expressed in only 6% of AML patients | No | Yes | Yes | [20] | ||
CD7 | Transmembrane glycoproteins, belonging to the immunoglobulin superfamily | Functions as a co-stimulatory receptor for T and B cell interactions during lymphocyte development, but function may be redundant | Phase I/II clinical trials on CAR-T in China | Activated T cells, NK cells, and some lymphoid and myeloid precursor cells | Expressed in 30% of adult AML patients | No (or transiently expressed) | Yes | Yes | [21] | ||
CD70 | Tumor necrosis factor receptor ligand for CD27, type II transmembrane glycoprotein | Tumor necrosis factor receptor | An early phase I clinical trial on CAR-T in China | Dendritic cells, B cells, upregulated on activated immune cells, monocytes and regulatory T cells expressed most | Overexpressed on solid tumors, lymphatic and myeloid tumors (including AML) | No | Yes | Yes | |||
ILT3 (LILRB4) | Immunoglobulin-like receptor B | Inhibition of T cell activation and proliferation; ILT3 expression on AML cells is thought to be used to bypass immune surveillance, particularly in the myeloid subtype | An early phase I clinical trial on CAR-T in China | Myeloid antigen presenting cells (including monocytes) | AML cells | No | Yes | Yes | |||
NKG2D ligand (NKG2DL) | NKG2D is a natural killer cell surface activating receptor (natural killer cell group 2 member D), a C-type lectin-like receptor protein | Activating receptors | Phase I clinical trials on CAR-NK in China and US | NKG2D ligand expression is limited in healthy tissues, mainly in NK cells, γδ T cells, CD8+ T lymphocytes, some CD4+ T cell subsets, Treg cells, endothelial cells, myeloid-derived suppressor cells | Upregulated in response to DNA damage, severe or malignant transformation; detected in hematological and solid tumors but is lowly expressed | No | Yes | Yes | |||
CD276 (B7-H3) | Transmembrane protein, a co-receptor belonging to the B7 family of immune checkpoint molecules | Immune checkpoint molecules | A clinical trial on CAR-T in China | Antigen presenting cells, HSCs (low expression) | Overexpression on primary AML cells, especially monocyte subtype; expressed in 39–80% of bone marrow samples from AML patients | Yes(low) | Unknown | Yes | [31] | ||
CD117 (c-kit) | Homologous receptor for stem cell factor (c-kit), type III tyrosine kinase receptor | Mast cell/stem cell growth factor receptor, which plays an important role in maintaining HSC homeostasis | The only one clinical trial on CAR-T in China was terminated because the therapeutic effect was not as expected | Gonadal, myeloid, erythroid precursor cells, HSCs, mast cells, melanocytes, Cajal mesenchymal cells, endothelial cells (e.g., skin, breast tissue) | Expressed on 80–90% of AML primary cells | Yes(high) | No | Yes | [32] | ||
FLT3 (CD135) | Fms-related receptor tyrosine kinase 3, type III cytokine receptor | Maintenance of normal hematopoietic stem cell and precursor cell functions, including proliferation and differentiation. Presence of FLT3 mutation indicates poor prognosis | Phase I/II clinical trials on CAR-T in China | CNS, small intestine, testis, HSCs | Expressed on 54–90% of AML primary cells | Yes | Yes(high) | Yes | |||
CD19 | Transmembrane proteins | Facilitates survival of B-cell development | A phase II/III clinical trial on CAR-T in Israel A phase I/II clinical trial on CAR-T in China | Prevalent in all stages of B cells except HSCs and plasma cells | There is a strong correlation between abnormal CD19 expression and t (8;21) in AML | No | Unknown | Yes | [36] | ||
CD174 (Lewis-Y, LeY) | Sphingolipids (diatomic glycosyltransferases) | Blood group antigens | A phase I clinical trial on CAR-T in Australia but with unknown status | Limited expression in normal tissues, mainly in small intestinal endothelial cells | Expressed in a wide range of solid and blood tumors | Yes | Possible | Yes | |||
CLL-1 (CLEC12A) | Type II membrane glycoprotein, C-type lectin-like molecule | Inhibitory receptors, involved in maintaining immune homeostasis | Phase I/II clinical trials on CAR-T in China and US Phase I clinical trials on CD33/CLL1 CAR-T in China An early Phase I clinical trial on CD33/CLL1 CAR-NK in China | Myeloid cells, myeloid precursor cells, lung tissue, gastrointestinal endothelial cells | Expressed on 78–92% of AML primary cells | Yes | Yes | Yes | |||
CD38 | Glycoproteins | Cyclic ADP-ribose hydrolase | Phase I/II clinical trials on CAR-T in China | NK cells, B cells, Plasma cells, HSCs (low expression) | Highly expressed on primary AML cells and plasma cells from multiple myeloma | Yes(low) | No | Yes | |||
CD44v6 | Glycoproteins | Intercellular, cell–matrix adhesion receptors | A phase I/II clinical trial on CAR-T in Czechia and Italy was terminated due to the lack of target’s expression and low patient recruitment | Widespread expression on multiple tissue types, activated T cells, monocytes, keratinocytes, but all expressed at low levels | Expression present in 60% of AML patients, relatively tumor specific | No | Unknown | Yes | [45] | ||
FRβ | Folate binding protein receptor | Assist with folic acid intake | Preclinical trials: no current clinical trials using FRβ CAR-T/NK | Myeloid cells, HSCs (low expression), activated macrophages | Expressed on 70% of AML primary cells, also upregulated with ATRA, HDAC | No | Yes | Yes | |||
GM-CSF (CD116/CD131) | Granulocyte–macrophage colony-stimulating factor | Granulocyte–macrophage colony-stimulating factor | Preclinical trials: no current clinical trials using GM-CSF CAR-T/NK | Myeloid cells | CD116 is expressed in 63–78% of AML patients, especially those with FLT3 mutations | Unknown | No | Yes | [48] | ||
CD25 (IL-2Rα) | Type I transmembrane protein | Unknown | Only used in ADC studies in phase I/II clinical trials. No current clinical trials using CD25 CAR-T/NK | T, B cells, thymocytes, myeloid precursor cells, oligodendrocytes | found in 25% of patients with AML | No | Yes | Yes | |||
CD32 | Immunoglobulin superfamily, glycoprotein | Unknown | No current clinical trials using CD32 CAR-T/NK | Monocytes, granulocytes, B cells, macrophages, platelets | Approximately 34% of people with AML express it | No | Yes | Yes | [52] | ||
CD47 | Immunoglobulin superfamily, glycoprotein | Binds SIRPa and inhibits cytophagy | Used in monoclonal antibody studies in phase I-III clinical trials. No current clinical trials using CD47 CAR-T/NK | Keratinocytes, immune cells | Expressed in almost all AML patients | Yes(low) | Yes | Yes | [53] | ||
CD56 | Neuronal cell adhesion molecule, glycoprotein | Unknown | A phase I/II clinical trial on CAR-T in China but was unknown status A clinical trial on CAR-T in China was terminated with unknown reasons | Keratinocytes, NK, T cells, nerve, neuroendocrine tissue | Expressed on AML primary cells and possibly on LSCs | No | Possible | Yes | [54] | ||
CD90 (Thy1) | Immunoglobulin superfamily, glycoprotein | Unknown | No current clinical trials using CD90 CAR-T/NK | Endothelial cells, neural tissue, thymocytes | Expressed on AML primary cells and possibly on LSCs | Yes | Possible | Yes | [55] | ||
CD96 | Type I transmembrane proteins, immunoglobulin superfamily | Modifications in T cell and natural killer cell adhesion | No current clinical trials using CD96 CAR-T/NK | T cells, NK cells, endothelial cells | Expressed on LSC, AML primary cells | Yes(low) | Yes | Yes | [56] | ||
IL1RAP | Auxiliary proteins | IL-1 receptor | A clinical trial on CAR-T in France | Liver, esophagus, gastrointestinal tissues, genitourinary tract tissues | Expressed on 80% of AML primary cells | No | Yes | Yes | [57] | ||
MUC1 | Glycoproteins | Mucosal protective effect, transmitting cellular signals | A phase I/II clinical trial on CAR-T in China but was unknown status | Expressed on most general epithelial cells and Treg cells, lymphoid tissue, lung endothelial cells, gastrointestinal endothelial cells, genitourinary tissues, placenta, skin | Expressed on LSC, AML primary cells | Yes(low) | Yes | Yes | [58] | ||
WT1 | Intracellular peptides, zinc finger DNA binding proteins | Endogenous antigens, transcription factors | A phase I clinical trial on CAR-T in China | Kidney, oviduct, endothelium, testis | Expressed on AML primary cells, LSC | Yes(low) | Yes | Yes | |||
PR1/HLA-A2 (h8F4) | Intracellular peptide. PR1 peptide derived from leukemia-associated antigen protease 3 and neutrophil elastase | Endogenous antigens | Preclinical trials: CAR-T targeting either PR1 or HLA-A2 have been shown to be effective in eliminating AML primary cells in in vitro trials. No current clinical trials using PR1/HLA-A2 CAR-T/NK | PR1 is present in primitive asplenophilic granules of neutrophils and HLA-A2 is overexpressed on primitive cells of the myeloid lineage | Expressed on AML primary cells | Yes | Yes | Yes | [62] | ||
CD93 | C-type lectin transmembrane receptor | Cell adhesion, host defense | Used in preclinical trials and vaccine trials. No current clinical trials using CD93 CAR-T/NK | Expressed on neutrophils, monocytes, mature myeloid cells, endothelial cells, but not on HSCs, other myeloid precursor cells, erythrocytes, TB lymphocytes, platelets | Expressed on AML primary cells | No | Unknown | Yes | [63] | ||
PD1 | PD1 is a member of the co-stimulatory receptor B7/CD28 family | When PD1 binds to its programmed death ligand 1 (PD-L1), it controls T-cell activation, stops T-cells from multiplying and making a lot of IFN-, TNF-, and IL-2, and makes it harder for T-cells to live. cTLA-4 also controls T-cell activation in a bad way | Used in monoclonal antibody studies in phase I/II clinical trials. No current clinical trials using PD1 CAR-T/NK | Activated T lymphocytes express PD-1 on their surface, in addition to other cells (e.g., B cells, NK cells, dendritic cells, macrophages, vascular endothelial cells, epithelial cells) | Upregulated expression of PD1 on the surface of bone marrow CD8+ T cells in AML patients | Unknown | Unknown | Yes | [64] | ||
PRAME | Intracellular peptides | Testicular tumor antigen | Used in TCR T-cell studies and vaccine trials in phase I/II clinical trials No current clinical trials using PRAME CAR-T/NK | CD8+ T cells | Expressed on 41–55% of AML primary cells | Yes(low) | Yes | Yes | [61] | ||
mLPA | Methyl-hemolytic phosphatidic acid | CD1c-restricted T-cell antigen | No current clinical trials using mLPA CAR-T/NK | monocytes, dendritic cells, TB lymphocytes | Found on AML primary cells, LSCs | No | Yes | Yes | [65] | ||
IDH1 (R132) | Isocitrate dehydrogenase 1, intracellular | Glycolic acid bypass, tricarboxylic acid cycle | Due to the intracellular presence of the antigen, it is temporarily impossible to attach it to the CAR. So, there is no current clinical trials using IDH1 CAR-T/NK | Hepatocytes, cytotrophoblasts | Expressed on AML primary cells, LSCs; in primary AML patients, expression is present in approximately 20% of patients | Yes | Yes | Yes | [66] | ||
IDH2 (R140) | Isocitrate dehydrogenase 2, intracellular | Glycolic acid bypass, tricarboxylic acid cycle | Due to the intracellular presence of the antigen, it is temporarily impossible to attach it to the CAR. So, there is no current clinical trials using IDH2 CAR-T/NK | Distal renal tubular cells, cytotrophoblasts | Expressed on AML primary cells, LSCs; about 20% of primary AML patients | Yes | Yes | Yes | |||
NPM1mut | Ribophilin 1 mutant | Ribosome biosynthesis, host-virus interactions | No current clinical trials using NPM1mut CAR-T/NK | Reduced specificity of cells and tissues | AML primary cells and LSCs express it | No | Yes | Yes | |||
NOTCH2 | NOTCH signaling molecule isoform 2 | Disease progression | No current clinical trials using NOTCH2 CAR-T/NK | Non-germline precursor cells, Paneth cells | Found in both primary cells and LSCs of AML | Yes | Yes | Yes | [70] | ||
PRL3 | Protein tyrosine phosphatase type Iva member 3 | Enhanced PI3K/Akt signaling activation | No current clinical trials using PRL3 CAR-T/NK | Cardiomyocytes, neutrophils, atypical monocytes | Expressed on AML primary cells, LSC | Yes | Yes | Yes | [61] | ||
IL12RB1 | IL-12 receptor beta 1 | Transmitting cytokine signals | No current clinical trials using IL12RB1 CAR-T/NK | T-cells, Kupffer cells, B-cells | Expressed on AML primary cells, LSC | Yes | Yes | Yes | [71] | ||
CD244/2B4 | NK cell activating/inhibitory receptor | NK cell-activated/inhibitory receptors | No current clinical trials using CD244/2B4 CAR-T/NK | Unknown | Expressed on both AML primary cells, LSC | Yes(high) | Yes(high) | Yes(high) | [72] | ||
RHAMM | Intracellular peptides | Cellular matrix interactions | Due to the intracellular presence of the antigen, it is temporarily impossible to attach it to the CAR. So, there is no current clinical trials using RHAMM CAR-T/NK | Colonic | Expressed in AML primary cells, possibly in LSCs | Yes | Possible | Yes | [73] | ||
Survivin | Intracellular peptides | Anti-apoptotic proteins (associated with embryogenesis) | Used in vaccine test. It is temporarily unable to attach antigen to CAR, so there are no current clinical trials using Survivin CAR-T/NK | Endothelial cells | Expressed on AML primary cells, LSC | Yes | Yes | Yes | |||
hTERT | Intracellular peptides | Telomerase complex subunit | Used in vaccine test. It is temporarily unable to attach antigen to CAR, so there are no current clinical trials using hTERT CAR-T/NK | Keratinocytes, testis, endothelial cells, placenta | Expressed in AML primary cells, possibly in LSC | Yes(low) | Possible | Yes | |||
CD4 | T lymphocyte membrane glycoprotein | Interaction with major histocompatibility complex class II antigens | No current clinical trials using CD4 CAR-T/NK are recruiting. But CD4 CAR-T is used in several phase I clinical trials for T cell malignancies or solid tumors in China and US | T-lymphocyte cells, and is expressed in nearly all T-cells | Expressed in 30%-40% of other AML subtypes, 65% of AML-M4, and 78.3% of AML-M5 | No | Yes | Yes | [79] | ||