Lentivirus-induced dendritic cells for immunization against high-risk WT1(+) acute myeloid leukemia.

2.50
Hdl Handle:
http://hdl.handle.net/10033/288407
Title:
Lentivirus-induced dendritic cells for immunization against high-risk WT1(+) acute myeloid leukemia.
Authors:
Sundarasetty, Bala Sai; Singh, Vijay Kumar; Salguero, Gustavo; Geffers, Robert ( 0000-0003-4409-016X ) ; Rickmann, Mareike; Macke, Laura; Borchers, Sylvia; Figueiredo, Constanca; Schambach, Axel; Gullberg, Urban; Provasi, Elena; Bonini, Chiara; Ganser, Arnold; Woelfel, Thomas; Stripecke, Renata
Abstract:
Wilms' tumor 1 antigen (WT1) is overexpressed in acute myeloid leukemia (AML), a high-risk neoplasm warranting development of novel immunotherapeutic approaches. Unfortunately, clinical immunotherapeutic use of WT1 peptides against AML has been inconclusive. With the rationale of stimulating multiantigenic responses against WT1, we genetically programmed long-lasting dendritic cells capable of producing and processing endogenous WT1 epitopes. A tricistronic lentiviral vector co-expressing a truncated form of WT1 (lacking the DNA-binding domain), granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin-4 (IL-4) was used to transduce human monocytes ex vivo. Overnight transduction induced self-differentiation of monocytes into immunophenotypically stable "SmartDC/tWT1" (GM-CSF(+), IL-4(+), tWT1(+), IL-6(+), IL-8(+), TNF-α(+), MCP-1(+), HLA-DR(+), CD86(+), CCR2(+), CCR5(+)) that were viable for 3 weeks in vitro. SmartDC/tWT1 were produced with peripheral blood mononuclear cells (PBMC) obtained from an FLT3-ITD(+) AML patient and surplus material from a donor lymphocyte infusion (DLI) and used to expand CD8(+) T cells in vitro. Expanded cytotoxic T lymphocytes (CTLs) showed antigen-specific reactivity against WT1 and against WT1(+) leukemia cells. SmartDC/tWT1 injected s.c. into Nod.Rag1(-/-).IL2rγc(-/-) mice were viable in vivo for more than three weeks. Migration of human T cells (huCTLs) to the immunization site was demonstrated following adoptive transfer of huCTLs into mice immunized with SmartDC/tWT1. Furthermore, SmartDC/tWT1 immunization plus adoptive transfer of T cells reactive against WT1 into mice resulted in growth arrest of a WT1(+) tumor. Gene array analyses of SmartDC/tWT1 demonstrated upregulation of several genes related to innate immunity. Thus, SmartDC/tWT1 can be produced in a single day of ex vivo gene transfer, are highly viable in vivo, and have great potential for use as immunotherapy against malignant transformation overexpressing WT1.
Affiliation:
Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, 30625 Hannover, Germany.
Citation:
Lentivirus-induced dendritic cells for immunization against high-risk WT1(+) acute myeloid leukemia. 2013, 24 (2):220-37 Hum. Gene Ther.
Journal:
Human gene therapy
Issue Date:
Feb-2013
URI:
http://hdl.handle.net/10033/288407
DOI:
10.1089/hum.2012.128
PubMed ID:
23311414
Type:
Article
Language:
en
ISSN:
1557-7422
Appears in Collections:
publications of the research group genomeanalytics (GMAK)

Full metadata record

DC FieldValue Language
dc.contributor.authorSundarasetty, Bala Saien_GB
dc.contributor.authorSingh, Vijay Kumaren_GB
dc.contributor.authorSalguero, Gustavoen_GB
dc.contributor.authorGeffers, Roberten_GB
dc.contributor.authorRickmann, Mareikeen_GB
dc.contributor.authorMacke, Lauraen_GB
dc.contributor.authorBorchers, Sylviaen_GB
dc.contributor.authorFigueiredo, Constancaen_GB
dc.contributor.authorSchambach, Axelen_GB
dc.contributor.authorGullberg, Urbanen_GB
dc.contributor.authorProvasi, Elenaen_GB
dc.contributor.authorBonini, Chiaraen_GB
dc.contributor.authorGanser, Arnolden_GB
dc.contributor.authorWoelfel, Thomasen_GB
dc.contributor.authorStripecke, Renataen_GB
dc.date.accessioned2013-05-02T11:03:32Zen
dc.date.available2013-05-02T11:03:32Zen
dc.date.issued2013-02en
dc.identifier.citationLentivirus-induced dendritic cells for immunization against high-risk WT1(+) acute myeloid leukemia. 2013, 24 (2):220-37 Hum. Gene Ther.en_GB
dc.identifier.issn1557-7422en
dc.identifier.pmid23311414en
dc.identifier.doi10.1089/hum.2012.128en
dc.identifier.urihttp://hdl.handle.net/10033/288407en
dc.description.abstractWilms' tumor 1 antigen (WT1) is overexpressed in acute myeloid leukemia (AML), a high-risk neoplasm warranting development of novel immunotherapeutic approaches. Unfortunately, clinical immunotherapeutic use of WT1 peptides against AML has been inconclusive. With the rationale of stimulating multiantigenic responses against WT1, we genetically programmed long-lasting dendritic cells capable of producing and processing endogenous WT1 epitopes. A tricistronic lentiviral vector co-expressing a truncated form of WT1 (lacking the DNA-binding domain), granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin-4 (IL-4) was used to transduce human monocytes ex vivo. Overnight transduction induced self-differentiation of monocytes into immunophenotypically stable "SmartDC/tWT1" (GM-CSF(+), IL-4(+), tWT1(+), IL-6(+), IL-8(+), TNF-α(+), MCP-1(+), HLA-DR(+), CD86(+), CCR2(+), CCR5(+)) that were viable for 3 weeks in vitro. SmartDC/tWT1 were produced with peripheral blood mononuclear cells (PBMC) obtained from an FLT3-ITD(+) AML patient and surplus material from a donor lymphocyte infusion (DLI) and used to expand CD8(+) T cells in vitro. Expanded cytotoxic T lymphocytes (CTLs) showed antigen-specific reactivity against WT1 and against WT1(+) leukemia cells. SmartDC/tWT1 injected s.c. into Nod.Rag1(-/-).IL2rγc(-/-) mice were viable in vivo for more than three weeks. Migration of human T cells (huCTLs) to the immunization site was demonstrated following adoptive transfer of huCTLs into mice immunized with SmartDC/tWT1. Furthermore, SmartDC/tWT1 immunization plus adoptive transfer of T cells reactive against WT1 into mice resulted in growth arrest of a WT1(+) tumor. Gene array analyses of SmartDC/tWT1 demonstrated upregulation of several genes related to innate immunity. Thus, SmartDC/tWT1 can be produced in a single day of ex vivo gene transfer, are highly viable in vivo, and have great potential for use as immunotherapy against malignant transformation overexpressing WT1.en_GB
dc.language.isoenen
dc.rightsArchived with thanks to Human gene therapyen_GB
dc.titleLentivirus-induced dendritic cells for immunization against high-risk WT1(+) acute myeloid leukemia.en
dc.typeArticleen
dc.contributor.departmentDepartment of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, 30625 Hannover, Germany.en_GB
dc.identifier.journalHuman gene therapyen_GB

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