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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 mice immunized with modified bone  marrow DCs after a tumor challenge. Animals were immunized with  bone marrow DCs modified with Adβgal or AdNull, followed 14 d later  by intravenous challenge of 105 CT26.CL25 tumor cells. The animals  were not killed, but were followed for survival. The data is expressed as  percentage of survival as a function of time. Survival for the mice immunized 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 <0.0001).
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Figure 9: Survival advantage in mice immunized with modified bone marrow DCs after a tumor challenge. Animals were immunized with bone marrow DCs modified with Adβgal or AdNull, followed 14 d later by intravenous challenge of 105 CT26.CL25 tumor cells. The animals were not killed, but were followed for survival. The data is expressed as percentage of survival as a function of time. Survival for the mice immunized 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 <0.0001).

Mentions: Consistent with the studies using XS52-Adβgal modified DCs, BALB/c mice that were immunized with bone marrow DC–Adβgal before challenge with tumor cells were effectively protected against the tumor challenge, as evidenced by a prolonged survival in the bone marrow DC–Adβgal group compared to the bone marrow DC–AdNull group (P <0.0001, Fig. 9). In contrast, mice immunized with bone marrow DC–Adβgal were not protected against a challenge by CT26.WT cells (P >0.9; not shown), indicating that the immune response was βgal specific.


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 mice immunized with modified bone  marrow DCs after a tumor challenge. Animals were immunized with  bone marrow DCs modified with Adβgal or AdNull, followed 14 d later  by intravenous challenge of 105 CT26.CL25 tumor cells. The animals  were not killed, but were followed for survival. The data is expressed as  percentage of survival as a function of time. Survival for the mice immunized 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 <0.0001).
© Copyright Policy
Related In: Results  -  Collection

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

Figure 9: Survival advantage in mice immunized with modified bone marrow DCs after a tumor challenge. Animals were immunized with bone marrow DCs modified with Adβgal or AdNull, followed 14 d later by intravenous challenge of 105 CT26.CL25 tumor cells. The animals were not killed, but were followed for survival. The data is expressed as percentage of survival as a function of time. Survival for the mice immunized 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 <0.0001).
Mentions: Consistent with the studies using XS52-Adβgal modified DCs, BALB/c mice that were immunized with bone marrow DC–Adβgal before challenge with tumor cells were effectively protected against the tumor challenge, as evidenced by a prolonged survival in the bone marrow DC–Adβgal group compared to the bone marrow DC–AdNull group (P <0.0001, Fig. 9). In contrast, mice immunized with bone marrow DC–Adβgal were not protected against a challenge by CT26.WT cells (P >0.9; not shown), indicating that the immune response was βgal specific.

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