title: Targeting of acute myeloid leukaemia by cytokine-induced killer cells redirected with a novel CD123-specific chimeric antigen receptor.
abstract: 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.
authors: Centro di Ricerca Matilde Tettamanti, Department of Paediatrics, University of Milano-Bicocca, San Gerardo Hospital, Monza, Italy.
authors: Sarah
authors: S
authors: Tettamanti
authors: Virna
authors: V
authors: Marin
authors: Irene
authors: I
authors: Pizzitola
authors: Chiara F
authors: CF
authors: Magnani
authors: Greta M P
authors: GM
authors: Giordano Attianese
authors: Elisabetta
authors: E
authors: Cribioli
authors: Francesca
authors: F
authors: Maltese
authors: Stefania
authors: S
authors: Galimberti
authors: Angel F
authors: AF
authors: Lopez
authors: Andrea
authors: A
authors: Biondi
authors: Dominique
authors: D
authors: Bonnet
authors: Ettore
authors: E
authors: Biagi
mesh_terms: D045744:Cell Line, Tumor / Q000378:metabolism; D018920:Coculture Techniques; D055612:Cytokine-Induced Killer Cells / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D003601:Cytotoxicity Tests, Immunologic; D042783:Endothelial Cells; D005260:Female; D057809:HEK293 Cells; D006412:Hematopoietic Stem Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D053650:Interleukin-3 Receptor alpha Subunit / Q000037:antagonists & inhibitors; D007948:Leukemia, Monocytic, Acute / Q000473:pathology; D015470:Leukemia, Myeloid, Acute / Q000473:pathology*; D015479:Leukemia, Myelomonocytic, Acute / Q000473:pathology*; D008297:Male; D009000:Monocytes; D011956:Receptors, Cell Surface / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D014161:Transduction, Genetic; D014410:Tumor Stem Cell Assay
chemical_list: D016207:Cytokines; C115022:IL3RA protein, human; D053650:Interleukin-3 Receptor alpha Subunit; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins