title: Efficacious immune therapy in chronic myelogenous leukemia (CML) recognizes antigens that are expressed on CML progenitor cells.
abstract: Curative effects of graft-versus-leukemia-based therapies such as donor lymphocyte infusion (DLI) for chronic myelogenous leukemia (CML) may result from immunologic ablation of self-renewing CML progenitor cells. Patients who achieved durable remissions after DLI developed a significant B-cell lymphocytosis after treatment, which did not occur in patients who were unresponsive to DLI. In this study, we identified antigen targets of this B-cell response by probing two immunoproteomic platforms with plasma immunoglobulins from seven CML patients with clinically apparent graft-versus-leukemia responses after DLI. In total, 62 antigens elicited greater reactivity from post-DLI versus pre-DLI plasma. Microarray analysis revealed that >70% of the antigens were expressed in CML CD34(+) cells, suggesting that expression in malignant progenitor cells is a feature common to antibody targets of DLI. We confirmed elevated expression of three target antigens (RAB38, TBCE, and DUSP12) in CML that together consistently elicited antibody responses in 18 of 21 of an additional cohort of CML patients with therapeutic responses, but not in normal donors and rarely in non-CML patients. In summary, immunologic targets of curative DLI responses include multiple antigens on CML progenitor cells, identifying them as potential immunogens for vaccination and/or monitoring of immunotherapeutics designed to eliminate myeloid leukemia stem cells.
authors.affiliation: Cancer Vaccine Center and Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Melinda A
authors.initials: MA
authors.lastname: Biernacki
authors.forename: Ovidiu
authors.initials: O
authors.lastname: Marina
authors.forename: Wandi
authors.initials: W
authors.lastname: Zhang
authors.forename: Fenglong
authors.initials: F
authors.lastname: Liu
authors.forename: Ingmar
authors.initials: I
authors.lastname: Bruns
authors.forename: Ann
authors.initials: A
authors.lastname: Cai
authors.forename: Donna
authors.initials: D
authors.lastname: Neuberg
authors.forename: Christine M
authors.initials: CM
authors.lastname: Canning
authors.forename: Edwin P
authors.initials: EP
authors.lastname: Alyea
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Soiffer
authors.forename: Vladimir
authors.initials: V
authors.lastname: Brusic
authors.forename: Jerome
authors.initials: J
authors.lastname: Ritz
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Wu
mesh_terms: D000328:Adult; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015153:Blotting, Western; D054637:Dual-Specificity Phosphatases / Q000235:genetics / Q000276:immunology; D005260:Female; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D015723:Gene Library; D020544:Graft vs Leukemia Effect / Q000276:immunology; D006801:Humans; D056724:Immunity, Humoral / Q000276:immunology; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics* / Q000276:immunology / Q000628:therapy; D017710:Lymphocyte Transfusion; D008297:Male; D008875:Middle Aged; D018832:Molecular Chaperones / Q000235:genetics / Q000276:immunology; D009363:Neoplasm Proteins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D040081:Protein Array Analysis / Q000379:methods; D016896:Treatment Outcome; D055815:Young Adult; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; C469270:TBCE protein, human; C489855:dual specificity phosphatase 12; D054637:Dual-Specificity Phosphatases; C412058:RAB38 protein, human; D020691:rab GTP-Binding Proteins