1. Targeting of acute myeloid leukaemia by cytokine-induced killer cells redirected with a novel CD123-specific chimeric antigen receptor
- Author
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Ettore Biagi, Chiara F. Magnani, Greta Maria Paola Giordano Attianese, Angel F. Lopez, Virna Marin, Irene Pizzitola, Sarah Tettamanti, Elisabetta Cribioli, Francesca Maltese, Andrea Biondi, Dominique Bonnet, Stefania Galimberti, Tettamanti, S, Marin, V, Pizzitola, I, Magnani, C, GIORDANO ATTIANESE, G, Cribioli, E, Maltese, F, Galimberti, S, Lopez, A, Biondi, A, Bonnet, D, and Biagi, E
- Subjects
AML, CD123, Chimeric Antigen Receptor ,Male ,medicine.medical_treatment ,Recombinant Fusion Proteins ,CD34 ,Interleukin-3 Receptor alpha Subunit ,Receptors, Cell Surface ,Biology ,Immunotherapy, Adoptive ,Leukemia, Myelomonocytic, Acute ,Monocytes ,Cytokine-Induced Killer Cells ,Antigen ,Transduction, Genetic ,hemic and lymphatic diseases ,Cell Line, Tumor ,medicine ,Human Umbilical Vein Endothelial Cells ,Humans ,Progenitor cell ,Tumor Stem Cell Assay ,Cytokine-induced killer cell ,Endothelial Cells ,Hematology ,Immunotherapy ,Cytotoxicity Tests, Immunologic ,Hematopoietic Stem Cells ,Chimeric antigen receptor ,Coculture Techniques ,Haematopoiesis ,Leukemia, Myeloid, Acute ,HEK293 Cells ,Immunology ,Leukemia, Monocytic, Acute ,Cytokines ,Female ,Stem cell - Abstract
Summary Current therapeutic regimens for acute myeloid leukaemia (AML) are still associated with high rates of relapse. Immunotherapy with T-cells genetically modified to express chimeric antigen receptors (CARs) represents an innovative approach. Here we investigated the targeting of the interleukin three receptor alpha (IL3RA; CD123) molecule, which is overexpressed on AML bulk population, CD34+ leukaemia progenitors, and leukaemia stem cells (LSC) compared to normal haematopoietic stem/progenitor cells (HSPCs), and whose overexpression is associated with poor prognosis. Cytokine-induced killer (CIK) cells were transduced with SFG-retroviral-vector encoding an anti-CD123 CAR. Transduced cells were able to strongly kill CD123+ cell lines, as well as primary AML blasts. Interestingly, secondary colony experiments demonstrated that anti-CD123.CAR preserved in vitro HSPCs, in contrast to a previously generated anti-CD33.CAR, while keeping an identical cytotoxicity profile towards AML. Furthermore, limited killing of normal monocytes and CD123-low-expressing endothelial cells was noted, thus indicating a low toxicity profile of the anti-CD123.CAR. Taken together, our results indicate that CD123-specific CARs strongly enhance anti-AML CIK functions, while sparing HSPCs and normal low-expressing antigen cells, paving the way to develop novel immunotherapy approaches for AML treatment.
- Published
- 2012