Here we provide 'proof of concept' for retargeting of UniCAR T cells to CD33- and/or CD123-positive acute myeloid leukemia blasts in vitro and in vivo.
We observed that markers important in homing, cell quiescence, and signal propagation such as CD44, CD96, CD90, WT-1, CD123 and CD25 were most significantly differentially expressed on Lin-/CD38-/CD34+ population in AML from their normal counterparts (P < 0.05, Mann-Whitney).
Here we describe the generation and characterization of a fully-human monoclonal antibody specific to CD123, a surface marker which is overexpressed in a variety of hematological disorders, including acute myeloid leukemia.
In a patient-derived xenograft model using NSG mice, the repopulating capacity of LSCs pretreated with SL-101 <i>in vitro</i> was significantly impaired.<b>Conclusions:</b> Our data define the mechanisms by which SL-101 targets AML and warrant further investigation of the clinical application of SL-101 and other CD123-targeting strategies in AML.<i></i>.
In conclusion, these recent studies strongly support CD123 as an important therapeutic target for the treatment of BPDCN, while a possible in the treatment of AML and other hematological malignancies will have to be evaluated by in the ongoing clinical studies.
In this study, the proportions of CD34(+)/CD38(-)/CD123(+) LSCs compartment co-expressing the three adhesion molecules, N-Cadherin, Tie2 and CD44, respectively, from AML patients before and after chemotherapy were analyzed.
We studied the CD34+CD38-CD123+ fraction in AML blasts at diagnosis, and its utility as a unique phenotype for minimal residual disease (MRD) of AML patients.
Conventional immunotherapy targets for AML such as CD33 and CD123 have been proposed as targets for chimeric antigen receptor (CAR)-engineered T-cells (CAR-T-cells), a therapy that has been highly successful in the treatment of B-cell leukemia and lymphoma.
In addition, blasts of patients with mutant nucleophosmin (NPM1) revealed significantly higher CD33 and CD123 expression pointing toward the possibility of minimal residual disease-guided interventions in mutated NPM1-positive AMLs.
Proportions of CD34+/CD38-/CD123+ and CD34+/CD38+/CD123+ LSCs compartment co-expressing an increased level of OPN could be enriched in AML cell lines and in patient's primary cells by CUR treatment.
These suggest that CD123 aptamer and CD123 aptamer-mediated targeted drug delivery system may have potential applications for selective delivery cytotoxic agents to CD123-expressing tumors in AML theranostics.
In conclusion, BPDCN in the bone marrow has a characteristic immunoprofile (CD4+, CD56+, CD123+, and TCL-1+) and appears to be commonly associated with myelodysplastic features and a high frequency of TET2 mutations in the absence of other mutations commonly observed in AML.
CARs comprised of these D domains mediate potent T cell activation and cytolysis of CD123-expressing target cells and induce complete durable remission in two AML xenograft models.
Ten months after transplantation, she relapsed with an AML with basophilic maturation characterized by CD45(low) CD33(high), CD117⁺, CD13(-/+), HLA Dr(high), CD123(high), and CD203c⁺ blast cells lacking expression of CD7, CD10, CD34, CD15, CD14, CD56, CD36, CD64, and cytoplasmic tryptase.
It was observed that (i) the level of CDw131 expression strictly correlated with the level of CD116 (GM-CSFalpha receptor chain) and CD123 (IL-3Ralpha chain); (ii) AMLs with high CDw131 expression were characterized by low CD34 expression and usually high CD11b, CD14 expression; (iii) AMLs with high CDw131 expression frequently co-expressed receptors for angiogenic growth factors (vascular endothelial growth factor R2, Tie-2); (iv) AMLs with high CDw131 expression were more cycling than those with low CDw131 expression; (v) AMLs with high CDw131 frequently displayed Feline Murine Sarcoma (FMS-related) tyrosine kinase 3 (FLT3) internal tandem duplication and constitutively activated Signal Transducer and Activator of Transcription-5 (STAT5).
Adoptive transfer of CD123.CAR or CD19.CAR lymphocytes led to a significant anti-tumor response against acute myelogenous leukemia (AML) and acute lymphoblastic leukemia (ALL) disseminated diseases in NSG mice.
Moreover, this study demonstrates for the first time that AZD7762 inhibitor targets the CD34(+)CD38(-)CD123(+) primitive leukemic progenitors, which are responsible for the majority of AML patients relapse.
Importantly, SL-401 was highly active even in cells expressing low levels of CD123, with minimal effect on modulation of the CD123 target in acute myeloid leukemia.