Lentiviral vector-mediated autonomous differentiation of mouse bone marrow cells into immunologically potent dendritic cell vaccines.
Approaches facilitating generation of dendritic cell (DC) vaccines for clinical trials and enhancing their viability, bio-distribution, and capacity to stimulate antigen-specific immune responses are critical for immunotherapy. We programmed mouse bone marrow (BM) cells with lentiviral vectors (LV-GI4) so that they produced granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4) in an autonomous manner. DC/LV-GI4 cells underwent autonomous trans-differentiation to yield typical phenotypic characteristics of DCs. DC/LV-GI4 cells that self-differentiated either ex vivo or in vivo showed persistent and robust viability and stimulated high influx of DCs into draining lymph nodes (LNs). The immunostimulatory efficacy of DC/LV-GI4 cells was evaluated using MART1 and TRP2 as co-expressed melanoma antigens. Mice vaccinated with DC/LV-GI4 cells that self-differentiated in vitro or in vivo produced potent antigen-specific responses against melanoma, which correlated with protective and long-term therapeutic anti-tumor effects. Thus, DC precursors can be genetically engineered after a single ex vivo manipulation, resulting in DC vaccines with improved activity.
Koya
Richard C
RC
Department of Surgery, Division of Surgical Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
Kimura
Takahiro
T
Ribas
Antoni
A
Rozengurt
Nora
N
Lawson
Gregory W
GW
Faure-Kumar
Emmanuelle
E
Wang
He-jing
HJ
Herschman
Harvey
H
Kasahara
Noriyuki
N
Stripecke
Renata
R
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000276:immunology / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology*; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D005822:Genetic Vectors / Q000235:genetics; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D007150:Immunohistochemistry; D016219:Immunotherapy, Adoptive / Q000379:methods; D015847:Interleukin-4 / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D058965:MART-1 Antigen; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009363:Neoplasm Proteins / Q000276:immunology / Q000378:metabolism; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism; D016133:Polymerase Chain Reaction; D016019:Survival Analysis; D014162:Transfection
D015703:Antigens, CD; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D058965:MART-1 Antigen; D008565:Membrane Proteins; C548668:Mlana protein, mouse; D009363:Neoplasm Proteins; D010446:Peptide Fragments; C500290:peptide SVYDFFVWL; D015847:Interleukin-4; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D008156:Luciferases