title: Route of administration influences the antitumor effects of bone marrow-derived dendritic cells engineered to produce interleukin-12 in a metastatic mouse prostate cancer model.
abstract: Gene-modified dendritic cells (DC) provide unique therapeutic strategies for prostate cancer; however, the comparative evaluation of specific delivery options using appropriate preclinical models has not been described. In this study, bone marrow-derived DC were genetically engineered to express high levels of interleukin-12 (IL-12) with or without the costimulatory molecule B7-1, by ex vivo infection with recombinant adenoviral vectors. We used an orthotopic metastatic mouse prostate cancer preclinical model (178-2 BMA) to compare two therapeutic protocols for DC delivery, in situ and subcutaneous. DC were generated from bone marrow of syngeneic 129/Sv mice by culturing in the presence of GM-CSF and IL-4. In vitro DC/IL-12 or DC/IL-12/B7 produced high levels of biologically active IL-12. In situ delivery of DC/IL-12 or DC/IL-12/B7 induced a significant suppression of primary tumor growth compared to DC/beta gal controls (P=.0328 and P=.0019, respectively), as well as reduced numbers of spontaneous lung metastatic nodules (P=.1404 and P=.0335, respectively). In survival experiments, in situ DC/IL-12 injection demonstrated a small but statistically significant advantage (P=.0041). Subcutaneous, tumor lysate pulsed DC/IL-12 significantly decreased tumor size (P=.0152) and increased survival (P=0.0433) compared to HBSS controls but the decrease in the number of spontaneous lung metastases did not achieve statistical significance. Both in situ and subcutaneous treatments enhanced cytolytic activities of natural killer (NK) cells and cytotoxic T lymphocytes (CTL). In this preclinical model, gene-modified DC-based intratumoral immunotherapy was shown to be an effective therapeutic strategy for locally advanced prostate cancer based on tumor growth suppression, inhibition of metastasis and survival improvement.
authors.affiliation: Scott Department of Urology, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Takashi
authors.initials: T
authors.lastname: Saika
authors.forename: Takefumi
authors.initials: T
authors.lastname: Satoh
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Kusaka
authors.forename: Shin
authors.initials: S
authors.lastname: Ebara
authors.forename: Vladimir B
authors.initials: VB
authors.lastname: Mouraviev
authors.forename: Terry L
authors.initials: TL
authors.lastname: Timme
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Thompson
mesh_terms: D000256:Adenoviridae; D000818:Animals; D018122:B7-1 Antigen / Q000096:biosynthesis / Q000235:genetics; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology; D002455:Cell Division / Q000187:drug effects; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism* / Q000637:transplantation*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D016219:Immunotherapy, Adoptive; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000235:genetics; D015847:Interleukin-4 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000276:immunology; D008297:Male; D051379:Mice; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D023822:Tissue Engineering; D014161:Transduction, Genetic
chemical_list: D018122:B7-1 Antigen; D018664:Interleukin-12; D015847:Interleukin-4; D016178:Granulocyte-Macrophage Colony-Stimulating Factor