title: Dual CD19 and CD123 targeting prevents antigen-loss relapses after CD19-directed immunotherapies.
abstract: Potent CD19-directed immunotherapies, such as chimeric antigen receptor T cells (CART) and blinatumomab, have drastically changed the outcome of patients with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL). However, CD19-negative relapses have emerged as a major problem that is observed in approximately 30% of treated patients. Developing approaches to preventing and treating antigen-loss escapes would therefore represent a vertical advance in the field. Here, we found that in primary patient samples, the IL-3 receptor α chain CD123 was highly expressed on leukemia-initiating cells and CD19-negative blasts in bulk B-ALL at baseline and at relapse after CART19 administration. Using intravital imaging in an antigen-loss CD19-negative relapse xenograft model, we determined that CART123, but not CART19, recognized leukemic blasts, established protracted synapses, and eradicated CD19-negative leukemia, leading to prolonged survival. Furthermore, combining CART19 and CART123 prevented antigen-loss relapses in xenograft models. Finally, we devised a dual CAR-expressing construct that combined CD19- and CD123-mediated T cell activation and demonstrated that it provides superior in vivo activity against B-ALL compared with single-expressing CART or pooled combination CART. In conclusion, these findings indicate that targeting CD19 and CD123 on leukemic blasts represents an effective strategy for treating and preventing antigen-loss relapses occurring after CD19-directed therapies.
authors: Marco
authors: M
authors: Ruella
authors: David M
authors: DM
authors: Barrett
authors: Saad S
authors: SS
authors: Kenderian
authors: Olga
authors: O
authors: Shestova
authors: Ted J
authors: TJ
authors: Hofmann
authors: Jessica
authors: J
authors: Perazzelli
authors: Michael
authors: M
authors: Klichinsky
authors: Vania
authors: V
authors: Aikawa
authors: Farzana
authors: F
authors: Nazimuddin
authors: Miroslaw
authors: M
authors: Kozlowski
authors: John
authors: J
authors: Scholler
authors: Simon F
authors: SF
authors: Lacey
authors: Jan J
authors: JJ
authors: Melenhorst
authors: Jennifer J D
authors: JJ
authors: Morrissette
authors: David A
authors: DA
authors: Christian
authors: Christopher A
authors: CA
authors: Hunter
authors: Michael
authors: M
authors: Kalos
authors: David L
authors: DL
authors: Porter
authors: Carl H
authors: CH
authors: June
authors: Stephan A
authors: SA
authors: Grupp
authors: Saar
authors: S
authors: Gill
mesh_terms: D000818:Animals; D018941:Antigens, CD19 / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D053650:Interleukin-3 Receptor alpha Subunit / Q000008:administration & dosage* / Q000378:metabolism*; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control; D014411:Neoplastic Stem Cells / Q000378:metabolism; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000008:administration & dosage*; D013601:T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D023041:Xenograft Model Antitumor Assays
chemical_list: D018941:Antigens, CD19; D000970:Antineoplastic Agents; C000604811:CD19 molecule, human; C000598123:CTL019 chimeric antigen receptor; C115022:IL3RA protein, human; D053650:Interleukin-3 Receptor alpha Subunit; D011948:Receptors, Antigen, T-Cell