title: PD-1 blockade by CT-011, anti-PD-1 antibody, enhances ex vivo T-cell responses to autologous dendritic cell/myeloma fusion vaccine.
abstract: We have developed a cancer vaccine in which autologous tumor is fused with dendritic cells (DCs) resulting in the presentation of tumor antigens in the context of DC-mediated costimulation. In clinical trials, immunologic responses have been observed, however responses may be muted by inhibitory pathways. The PD1/PDL1 pathway is an important element contributing to tumor-mediated immune suppression. In this study, we demonstrate that myeloma cells and DC/tumor fusions strongly express PD-L1. Compared with a control population of normal volunteers, increased PD-1 expression was observed on T cells isolated from patients with myeloma. It is interesting to note that after autologous transplantation, T-cell expression of PD-1 returned to levels seen in normal controls. We examined the effect of PD-1 blockade on T-cell response to DC/tumor fusions ex vivo. Presence of CT-011, an anti-PD1 antibody, promoted the vaccine-induced T-cell polarization towards an activated phenotype expressing Th1 compared with Th2 cytokines. A concomitant decrease in regulatory T cells and enhanced killing in a cytotoxicity assay was observed. In summary, we demonstrate that PD-1 expression is increased in T cells of patients with active myeloma, and that CT-011 enhances activated T-cell responses after DC/tumor fusion stimulation.
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. jrosenb1@bidmc.harvard.edu
authors.forename: Jacalyn
authors.initials: J
authors.lastname: Rosenblatt
authors.forename: Brett
authors.initials: B
authors.lastname: Glotzbecker
authors.forename: Heidi
authors.initials: H
authors.lastname: Mills
authors.forename: Baldev
authors.initials: B
authors.lastname: Vasir
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Tzachanis
authors.forename: James D
authors.initials: JD
authors.lastname: Levine
authors.forename: Robin M
authors.initials: RM
authors.lastname: Joyce
authors.forename: Kerry
authors.initials: K
authors.lastname: Wellenstein
authors.forename: Whitney
authors.initials: W
authors.lastname: Keefe
authors.forename: Michael
authors.initials: M
authors.lastname: Schickler
authors.forename: Rinat
authors.initials: R
authors.lastname: Rotem-Yehudar
authors.forename: Donald
authors.initials: D
authors.lastname: Kufe
authors.forename: David
authors.initials: D
authors.lastname: Avigan
mesh_terms: D000888:Antibodies, Anti-Idiotypic / Q000276:immunology; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D060890:B7-H1 Antigen; D019496:Cancer Vaccines / Q000276:immunology / Q000494:pharmacology; D002459:Cell Fusion; D049109:Cell Proliferation / Q000187:drug effects; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D066298:In Vitro Techniques; D007963:Leukocytes, Mononuclear / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D009101:Multiple Myeloma / Q000276:immunology* / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D061026:Programmed Cell Death 1 Receptor; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D058408:Th1-Th2 Balance / Q000187:drug effects; D014182:Transplantation, Autologous
chemical_list: D000888:Antibodies, Anti-Idiotypic; D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D019496:Cancer Vaccines; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor