title: Preclinical targeting of human acute myeloid leukemia and myeloablation using chimeric antigen receptor-modified T cells.
abstract: Many patients with acute myeloid leukemia (AML) are incurable with chemotherapy and may benefit from novel approaches. One such approach involves the transfer of T cells engineered to express chimeric antigen receptors (CARs) for a specific cell-surface antigen. This strategy depends upon preferential expression of the target on tumor cells. To date, the lack of AML-specific surface markers has impeded development of such CAR-based approaches. CD123, the transmembrane α chain of the interleukin-3 receptor, is expressed in the majority of AML cells but is also expressed in many normal hematopoietic cells. Here, we show that CD123 is a good target for AML-directed CAR therapy, because its expression increases over time in vivo even in initially CD123(dim) populations, and that human CD123-redirected T cells (CART123) eradicate primary AML in immunodeficient mice. CART123 also eradicated normal human myelopoiesis, a surprising finding because anti-CD123 antibody-based strategies have been reportedly well tolerated. Because AML is likely preceded by clonal evolution in "preleukemic" hematopoietic stem cells, our observations support CART123 as a viable AML therapy, suggest that CART123-based myeloablation may be used as a novel conditioning regimen for hematopoietic cell transplantation, and raise concerns for the use of CART123 without such a rescue strategy.
authors.affiliation: Abramson Cancer Center.
authors.forename: Saar
authors.initials: S
authors.lastname: Gill
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Tasian
authors.forename: Marco
authors.initials: M
authors.lastname: Ruella
authors.forename: Olga
authors.initials: O
authors.lastname: Shestova
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.forename: David L
authors.initials: DL
authors.lastname: Porter
authors.forename: Martin
authors.initials: M
authors.lastname: Carroll
authors.forename: Gwenn
authors.initials: G
authors.lastname: Danet-Desnoyers
authors.forename: John
authors.initials: J
authors.lastname: Scholler
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Grupp
authors.forename: Carl H
authors.initials: CH
authors.lastname: June
authors.forename: Michael
authors.initials: M
authors.lastname: Kalos
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D053650:Interleukin-3 Receptor alpha Subunit / Q000276:immunology*; D015470:Leukemia, Myeloid, Acute / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000637:transplantation*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000951:Antigens, Neoplasm; C115022:IL3RA protein, human; D053650:Interleukin-3 Receptor alpha Subunit; D011948:Receptors, Antigen, T-Cell