title: Generation of functional CLL-specific cord blood CTL using CD40-ligated CLL APC.
abstract: Though remissions have been observed following allo-HSCT for the treatment of CLL, many CLL patients are ineligible for transplant due to the lack of HLA-compatible donors. The use of umbilical cord blood (UCB) permits transplantation of many patients who lack HLA-compatible donors due to reduced requirements for stringent HLA matching between graft and recipient; however, disease relapse remains a concern with this modality. The generation of CLL-specific CTL from UCB T-cells, primed and expanded against the leukemic clone, might enhance the GVL effect and improve outcomes with UCB transplantation. Here we report the generation of functional, CLL-specific CTL using CD40-ligated CLL cells to prime partially-HLA matched UCB T-cells. Functionality and specificity were demonstrated by immune synapse assay, IFN-γ ELISpot, multi-parametric intracellular cytokine flow cytometry, and (51)Cr release assay. The use of patient-specific, non-CLL controls demonstrated the generation of both alloantigen and CLL-specific responses. Subsequently, we developed a clinically-applicable procedure permitting separation of alloreactive CTL from leukemia-specific CTL. Leukemia-specific CTL were able to mediate in vivo killing of CLL in humanized mice without concurrent or subsequent development of xenoGVHD. Our results demonstrate that generation of CLL-specific effectors from UCB is feasible and practical, and the results support further exploration of this strategy as a treatment modality for CLL.
authors.affiliation: Baylor College of Medicine, Department of Pathology and Immunology, Houston, Texas, United States of America. decker@bcm.edu
authors.forename: William K
authors.initials: WK
authors.lastname: Decker
authors.forename: Nina
authors.initials: N
authors.lastname: Shah
authors.forename: Dongxia
authors.initials: D
authors.lastname: Xing
authors.forename: Ruth
authors.initials: R
authors.lastname: Lapushin
authors.forename: Sufang
authors.initials: S
authors.lastname: Li
authors.forename: Simon N
authors.initials: SN
authors.lastname: Robinson
authors.forename: Hong
authors.initials: H
authors.lastname: Yang
authors.forename: Simrit
authors.initials: S
authors.lastname: Parmar
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Halpert
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Keating
authors.forename: John G
authors.initials: JG
authors.lastname: Gribben
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Molldrem
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Shpall
authors.forename: William G
authors.initials: WG
authors.lastname: Wierda
mesh_terms: D000328:Adult; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology* / Q000378:metabolism*; D000951:Antigens, Neoplasm / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology / Q000378:metabolism*; D005240:Feasibility Studies; D005312:Fetal Blood / Q000276:immunology*; D006680:HLA Antigens / Q000276:immunology; D006801:Humans; D054992:Immunological Synapses / Q000276:immunology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology*; D051379:Mice; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; D019013:CD40 Antigens; D006680:HLA Antigens