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

Takashi Saika, Takefumi Satoh, Nobuyuki Kusaka, Shin Ebara, Vladimir B. Mouraviev, Terry L. Timme, Timothy C. Thompson

Research output: Contribution to journalArticle

26 Citations (Scopus)

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/βgal 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.

Original languageEnglish
Pages (from-to)317-324
Number of pages8
JournalCancer Gene Therapy
Volume11
Issue number5
DOIs
Publication statusPublished - May 2004
Externally publishedYes

Fingerprint

Interleukin-12
Dendritic Cells
Prostatic Neoplasms
Bone Marrow
Neoplasms
CD80 Antigens
129 Strain Mouse
Neoplasm Metastasis
Lung
Cytotoxic T-Lymphocytes
Therapeutics
Granulocyte-Macrophage Colony-Stimulating Factor
Growth
Natural Killer Cells
Interleukin-4
Immunotherapy
Genes

Keywords

  • Dendritic cell
  • Immunotherapy
  • Interleukin-12
  • Prostate cancer

ASJC Scopus subject areas

  • Cancer Research
  • Genetics

Cite this

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. / Saika, Takashi; Satoh, Takefumi; Kusaka, Nobuyuki; Ebara, Shin; Mouraviev, Vladimir B.; Timme, Terry L.; Thompson, Timothy C.

In: Cancer Gene Therapy, Vol. 11, No. 5, 05.2004, p. 317-324.

Research output: Contribution to journalArticle

Saika, Takashi ; Satoh, Takefumi ; Kusaka, Nobuyuki ; Ebara, Shin ; Mouraviev, Vladimir B. ; Timme, Terry L. ; Thompson, Timothy C. / 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. In: Cancer Gene Therapy. 2004 ; Vol. 11, No. 5. pp. 317-324.
@article{17efa2a803564e11aa0570811f887558,
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/βgal 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.",
keywords = "Dendritic cell, Immunotherapy, Interleukin-12, Prostate cancer",
author = "Takashi Saika and Takefumi Satoh and Nobuyuki Kusaka and Shin Ebara and Mouraviev, {Vladimir B.} and Timme, {Terry L.} and Thompson, {Timothy C.}",
year = "2004",
month = "5",
doi = "10.1038/sj.cgt.7700709",
language = "English",
volume = "11",
pages = "317--324",
journal = "Cancer Gene Therapy",
issn = "0929-1903",
publisher = "Nature Publishing Group",
number = "5",

}

TY - JOUR

T1 - 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

AU - Saika, Takashi

AU - Satoh, Takefumi

AU - Kusaka, Nobuyuki

AU - Ebara, Shin

AU - Mouraviev, Vladimir B.

AU - Timme, Terry L.

AU - Thompson, Timothy C.

PY - 2004/5

Y1 - 2004/5

N2 - 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/βgal 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.

AB - 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/βgal 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.

KW - Dendritic cell

KW - Immunotherapy

KW - Interleukin-12

KW - Prostate cancer

UR - http://www.scopus.com/inward/record.url?scp=2342576353&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=2342576353&partnerID=8YFLogxK

U2 - 10.1038/sj.cgt.7700709

DO - 10.1038/sj.cgt.7700709

M3 - Article

C2 - 15044961

AN - SCOPUS:2342576353

VL - 11

SP - 317

EP - 324

JO - Cancer Gene Therapy

JF - Cancer Gene Therapy

SN - 0929-1903

IS - 5

ER -