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Dendritic cells genetically modified with an adenovirus vector encoding the cDNA for a model antigen induce protective and therapeutic antitumor immunity.

Song W, Kong HL, Carpenter H, Torii H, Granstein R, Rafii S, Moore MA, Crystal RG - J. Exp. Med. (1997)

Bottom Line: Dendritic cells (DCs) are potent antigen-presenting cells that play a critical role in the initiation of antitumor immune responses.In this study, we show that genetic modifications of a murine epidermis-derived DC line and primary bone marrow-derived DCs to express a model antigen beta-galactosidase (betagal) can be achieved through the use of a replication-deficient, recombinant adenovirus vector, and that the modified DCs are capable of eliciting antigen-specific, MHC-restricted CTL responses.Importantly, using a murine metastatic lung tumor model with syngeneic colon carcinoma cells expressing betagal, we show that immunization of mice with the genetically modified DC line or bone marrow DCs confers potent protection against a lethal tumor challenge, as well as suppression of preestablished tumors, resulting in a significant survival advantage.

View Article: PubMed Central - PubMed

Affiliation: Division of Pulmonary and Critical Care Medicine, The New York Hospital-Cornell Medical Center 10021, USA.

ABSTRACT
Dendritic cells (DCs) are potent antigen-presenting cells that play a critical role in the initiation of antitumor immune responses. In this study, we show that genetic modifications of a murine epidermis-derived DC line and primary bone marrow-derived DCs to express a model antigen beta-galactosidase (betagal) can be achieved through the use of a replication-deficient, recombinant adenovirus vector, and that the modified DCs are capable of eliciting antigen-specific, MHC-restricted CTL responses. Importantly, using a murine metastatic lung tumor model with syngeneic colon carcinoma cells expressing betagal, we show that immunization of mice with the genetically modified DC line or bone marrow DCs confers potent protection against a lethal tumor challenge, as well as suppression of preestablished tumors, resulting in a significant survival advantage. We conclude that genetic modification of DCs to express antigens that are also expressed in tumors can lead to antigen-specific, antitumor killer cells, with a concomitant resistance to tumor challenge and a decrease in the size of existing tumors.

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Survival advantage in tumor-bearing mice treated with modified bone marrow DCs. 3 d after the establishment of lung metastases with  intravenous administration of 3 × 104 CT26.CL25 tumor cells, BALB/c  mice were immunized with bone marrow DCs modified with Adβgal or  AdNull. The animals were not killed, but were followed for survival. The  data is expressed as percent survival as a function of time. Survival for  mice that were treated with bone marrow DC–Adβgal was significantly  prolonged over the bone marrow DC–AdNull control, as determined by  log-rank analysis of the Kaplan-Meier survival curves (P <0.002).
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Figure 10: Survival advantage in tumor-bearing mice treated with modified bone marrow DCs. 3 d after the establishment of lung metastases with intravenous administration of 3 × 104 CT26.CL25 tumor cells, BALB/c mice were immunized with bone marrow DCs modified with Adβgal or AdNull. The animals were not killed, but were followed for survival. The data is expressed as percent survival as a function of time. Survival for mice that were treated with bone marrow DC–Adβgal was significantly prolonged over the bone marrow DC–AdNull control, as determined by log-rank analysis of the Kaplan-Meier survival curves (P <0.002).

Mentions: Mice with preexisting lung metastases that received bone marrow DC–Adβgal treatment lived significantly longer than the bone marrow DC–AdNull control group (P <0.002, Fig. 10), demonstrating that primary DCs that are genetically modified to express the tumor antigen could suppress preestablished tumors. As in the prevention experiment, bone marrow DC–Adβgal immunization had no therapeutic effect on CT26.WT tumors that did not express βgal (P >0.5; not shown), indicating that the antitumor effect was tumor antigen specific. Similarly, lysed bone marrow DCs were ineffective in prolonging survival compared to control groups (P >0.1; not shown).


Dendritic cells genetically modified with an adenovirus vector encoding the cDNA for a model antigen induce protective and therapeutic antitumor immunity.

Song W, Kong HL, Carpenter H, Torii H, Granstein R, Rafii S, Moore MA, Crystal RG - J. Exp. Med. (1997)

Survival advantage in tumor-bearing mice treated with modified bone marrow DCs. 3 d after the establishment of lung metastases with  intravenous administration of 3 × 104 CT26.CL25 tumor cells, BALB/c  mice were immunized with bone marrow DCs modified with Adβgal or  AdNull. The animals were not killed, but were followed for survival. The  data is expressed as percent survival as a function of time. Survival for  mice that were treated with bone marrow DC–Adβgal was significantly  prolonged over the bone marrow DC–AdNull control, as determined by  log-rank analysis of the Kaplan-Meier survival curves (P <0.002).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2199096&req=5

Figure 10: Survival advantage in tumor-bearing mice treated with modified bone marrow DCs. 3 d after the establishment of lung metastases with intravenous administration of 3 × 104 CT26.CL25 tumor cells, BALB/c mice were immunized with bone marrow DCs modified with Adβgal or AdNull. The animals were not killed, but were followed for survival. The data is expressed as percent survival as a function of time. Survival for mice that were treated with bone marrow DC–Adβgal was significantly prolonged over the bone marrow DC–AdNull control, as determined by log-rank analysis of the Kaplan-Meier survival curves (P <0.002).
Mentions: Mice with preexisting lung metastases that received bone marrow DC–Adβgal treatment lived significantly longer than the bone marrow DC–AdNull control group (P <0.002, Fig. 10), demonstrating that primary DCs that are genetically modified to express the tumor antigen could suppress preestablished tumors. As in the prevention experiment, bone marrow DC–Adβgal immunization had no therapeutic effect on CT26.WT tumors that did not express βgal (P >0.5; not shown), indicating that the antitumor effect was tumor antigen specific. Similarly, lysed bone marrow DCs were ineffective in prolonging survival compared to control groups (P >0.1; not shown).

Bottom Line: Dendritic cells (DCs) are potent antigen-presenting cells that play a critical role in the initiation of antitumor immune responses.In this study, we show that genetic modifications of a murine epidermis-derived DC line and primary bone marrow-derived DCs to express a model antigen beta-galactosidase (betagal) can be achieved through the use of a replication-deficient, recombinant adenovirus vector, and that the modified DCs are capable of eliciting antigen-specific, MHC-restricted CTL responses.Importantly, using a murine metastatic lung tumor model with syngeneic colon carcinoma cells expressing betagal, we show that immunization of mice with the genetically modified DC line or bone marrow DCs confers potent protection against a lethal tumor challenge, as well as suppression of preestablished tumors, resulting in a significant survival advantage.

View Article: PubMed Central - PubMed

Affiliation: Division of Pulmonary and Critical Care Medicine, The New York Hospital-Cornell Medical Center 10021, USA.

ABSTRACT
Dendritic cells (DCs) are potent antigen-presenting cells that play a critical role in the initiation of antitumor immune responses. In this study, we show that genetic modifications of a murine epidermis-derived DC line and primary bone marrow-derived DCs to express a model antigen beta-galactosidase (betagal) can be achieved through the use of a replication-deficient, recombinant adenovirus vector, and that the modified DCs are capable of eliciting antigen-specific, MHC-restricted CTL responses. Importantly, using a murine metastatic lung tumor model with syngeneic colon carcinoma cells expressing betagal, we show that immunization of mice with the genetically modified DC line or bone marrow DCs confers potent protection against a lethal tumor challenge, as well as suppression of preestablished tumors, resulting in a significant survival advantage. We conclude that genetic modification of DCs to express antigens that are also expressed in tumors can lead to antigen-specific, antitumor killer cells, with a concomitant resistance to tumor challenge and a decrease in the size of existing tumors.

Show MeSH
Related in: MedlinePlus