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Immunostimulatory Gene Therapy Using Oncolytic Viruses as Vehicles.

Loskog A - Viruses (2015)

Bottom Line: Hence, like a Trojan horse, the gene vehicle can carry warriors and weapons into enemy territory to combat the tumor from within.In parallel, oncolytic viruses have been shown to be safe in patients.To prolong immune stimulation and to increase efficacy, these two fields are now merging and oncolytic viruses are armed with immunostimulatory transgenes.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Rudbeck laboratory C11, Dag Hammarskjoldsvag 20, 75185 Uppsala, Sweden. angelica.loskog@igp.uu.se.

ABSTRACT
Immunostimulatory gene therapy has been developed during the past twenty years. The aim of immunostimulatory gene therapy is to tilt the suppressive tumor microenvironment to promote anti-tumor immunity. Hence, like a Trojan horse, the gene vehicle can carry warriors and weapons into enemy territory to combat the tumor from within. The most promising immune stimulators are those activating and sustaining Th1 responses, but even if potent effects were seen in preclinical models, many clinical trials failed to show objective responses in cancer patients. However, with new tools to control ongoing immunosuppression in cancer patients, immunostimulatory gene therapy is now emerging as an interesting option. In parallel, oncolytic viruses have been shown to be safe in patients. To prolong immune stimulation and to increase efficacy, these two fields are now merging and oncolytic viruses are armed with immunostimulatory transgenes. These novel agents are racing towards approval as established cancer immunotherapeutics.

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The tumor microenvironment consists of both tumor cells and other cell types such as immature myeloid-derived suppressor cells (MDSC), M2 macrophages and T regulatory cells (Treg). These cells act together to promote tumor progression and suppress anti-tumor immune reactions. The aim of immunostimulatory gene therapy is to shift the ongoing immunosuppression towards Th1 immunity by activating dendritic cells (DCs), T helper (Th)-1 cells and cytotoxic T lymphocytes (CTLs) to induce tumor-specific killing by lymphocytes. PGE2: prostaglandin E2; IL: interleukin; VEGF: vascular endothelial growth factor; TGFβ: transforming growth factor β; Arg1: arginase 1; MPO: myeloperoxidase; CD40L: CD40 ligand.
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viruses-07-02899-f001: The tumor microenvironment consists of both tumor cells and other cell types such as immature myeloid-derived suppressor cells (MDSC), M2 macrophages and T regulatory cells (Treg). These cells act together to promote tumor progression and suppress anti-tumor immune reactions. The aim of immunostimulatory gene therapy is to shift the ongoing immunosuppression towards Th1 immunity by activating dendritic cells (DCs), T helper (Th)-1 cells and cytotoxic T lymphocytes (CTLs) to induce tumor-specific killing by lymphocytes. PGE2: prostaglandin E2; IL: interleukin; VEGF: vascular endothelial growth factor; TGFβ: transforming growth factor β; Arg1: arginase 1; MPO: myeloperoxidase; CD40L: CD40 ligand.

Mentions: It has been known for decades that the immune system can recognize and eradicate malignant cells. Different types of immunotherapies have been evaluated in an attempt to boost the ongoing anti-tumor responses. Treatments like interferons, granulocyte macrophage-colony stimulating factor (GM-CSF) and bacillus Calmette-Guérin (BCG) were the first approved immunotherapeutics but with high toxicity or questionable response rates. Nevertheless, BCG has been approved for more than 30 years for superficial bladder cancer since it significantly prolongs the relapse free intervals in this indication [1]. Unfortunately, the tumor and its microenvironment counteract immune responses by inducing immunosuppressive cells like M2 macrophages, myeloid-derived suppressor cells (MDSCs) and T regulatory cells (Tregs) [2,3] (Figure 1). In the tumor milieu, activated cytotoxic T lymphocytes (CTLs) are rapidly suppressed by these cells and become anergic, a state of reversible unresponsiveness, or die. In experimental settings, many immunotherapies have been evaluated, but real success has been absent until the patients were preconditioned with chemotherapy and/or irradiation to remove some of the immunosuppressive cells prior to immunotherapy. For example, the treatment of malignant melanoma using autologous ex vivo expanded tumor-infiltrating T lymphocytes was not effective but when combined with preconditioning the objective response rates reached 72% [4]. Gene engineered chimeric antigen receptor (CAR) T lymphocytes have also shown spectacular results in B cell malignancy after the introduction of preconditioning strategies [5]. A different approach is to block the inhibitory signaling that would otherwise restrain CTLs by using checkpoint blockade antibodies targeting CTLA-4 (CTL-associated protein 4) or PD-1/PD-L1 (Programmed death-ligand 1 and its receptor) [6]. Naturally occurring anti-tumor T lymphocytes previously controlled by immune evasion strategies are then released from restraint and can recognize and kill tumor cells. Checkpoint blockade antibody treatment is now approved for many cancers [6,7] and the next step is to combine this “release of the break” treatment with activating immunotherapies to reach long-term anti-tumor immunity and increase the complete response rates in the patients. Hence, the essence of cancer immunotherapy is to break tumor tolerance (e.g., break anergy) and to revert the ongoing suppressive responses to instead activate anti-tumor immunity. Novel concepts to treat cancer by stimulating the immune system are currently being investigated. One of these concepts is immunostimulatory gene therapy utilizing viruses as gene delivery vehicles [8].


Immunostimulatory Gene Therapy Using Oncolytic Viruses as Vehicles.

Loskog A - Viruses (2015)

The tumor microenvironment consists of both tumor cells and other cell types such as immature myeloid-derived suppressor cells (MDSC), M2 macrophages and T regulatory cells (Treg). These cells act together to promote tumor progression and suppress anti-tumor immune reactions. The aim of immunostimulatory gene therapy is to shift the ongoing immunosuppression towards Th1 immunity by activating dendritic cells (DCs), T helper (Th)-1 cells and cytotoxic T lymphocytes (CTLs) to induce tumor-specific killing by lymphocytes. PGE2: prostaglandin E2; IL: interleukin; VEGF: vascular endothelial growth factor; TGFβ: transforming growth factor β; Arg1: arginase 1; MPO: myeloperoxidase; CD40L: CD40 ligand.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4664972&req=5

viruses-07-02899-f001: The tumor microenvironment consists of both tumor cells and other cell types such as immature myeloid-derived suppressor cells (MDSC), M2 macrophages and T regulatory cells (Treg). These cells act together to promote tumor progression and suppress anti-tumor immune reactions. The aim of immunostimulatory gene therapy is to shift the ongoing immunosuppression towards Th1 immunity by activating dendritic cells (DCs), T helper (Th)-1 cells and cytotoxic T lymphocytes (CTLs) to induce tumor-specific killing by lymphocytes. PGE2: prostaglandin E2; IL: interleukin; VEGF: vascular endothelial growth factor; TGFβ: transforming growth factor β; Arg1: arginase 1; MPO: myeloperoxidase; CD40L: CD40 ligand.
Mentions: It has been known for decades that the immune system can recognize and eradicate malignant cells. Different types of immunotherapies have been evaluated in an attempt to boost the ongoing anti-tumor responses. Treatments like interferons, granulocyte macrophage-colony stimulating factor (GM-CSF) and bacillus Calmette-Guérin (BCG) were the first approved immunotherapeutics but with high toxicity or questionable response rates. Nevertheless, BCG has been approved for more than 30 years for superficial bladder cancer since it significantly prolongs the relapse free intervals in this indication [1]. Unfortunately, the tumor and its microenvironment counteract immune responses by inducing immunosuppressive cells like M2 macrophages, myeloid-derived suppressor cells (MDSCs) and T regulatory cells (Tregs) [2,3] (Figure 1). In the tumor milieu, activated cytotoxic T lymphocytes (CTLs) are rapidly suppressed by these cells and become anergic, a state of reversible unresponsiveness, or die. In experimental settings, many immunotherapies have been evaluated, but real success has been absent until the patients were preconditioned with chemotherapy and/or irradiation to remove some of the immunosuppressive cells prior to immunotherapy. For example, the treatment of malignant melanoma using autologous ex vivo expanded tumor-infiltrating T lymphocytes was not effective but when combined with preconditioning the objective response rates reached 72% [4]. Gene engineered chimeric antigen receptor (CAR) T lymphocytes have also shown spectacular results in B cell malignancy after the introduction of preconditioning strategies [5]. A different approach is to block the inhibitory signaling that would otherwise restrain CTLs by using checkpoint blockade antibodies targeting CTLA-4 (CTL-associated protein 4) or PD-1/PD-L1 (Programmed death-ligand 1 and its receptor) [6]. Naturally occurring anti-tumor T lymphocytes previously controlled by immune evasion strategies are then released from restraint and can recognize and kill tumor cells. Checkpoint blockade antibody treatment is now approved for many cancers [6,7] and the next step is to combine this “release of the break” treatment with activating immunotherapies to reach long-term anti-tumor immunity and increase the complete response rates in the patients. Hence, the essence of cancer immunotherapy is to break tumor tolerance (e.g., break anergy) and to revert the ongoing suppressive responses to instead activate anti-tumor immunity. Novel concepts to treat cancer by stimulating the immune system are currently being investigated. One of these concepts is immunostimulatory gene therapy utilizing viruses as gene delivery vehicles [8].

Bottom Line: Hence, like a Trojan horse, the gene vehicle can carry warriors and weapons into enemy territory to combat the tumor from within.In parallel, oncolytic viruses have been shown to be safe in patients.To prolong immune stimulation and to increase efficacy, these two fields are now merging and oncolytic viruses are armed with immunostimulatory transgenes.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Rudbeck laboratory C11, Dag Hammarskjoldsvag 20, 75185 Uppsala, Sweden. angelica.loskog@igp.uu.se.

ABSTRACT
Immunostimulatory gene therapy has been developed during the past twenty years. The aim of immunostimulatory gene therapy is to tilt the suppressive tumor microenvironment to promote anti-tumor immunity. Hence, like a Trojan horse, the gene vehicle can carry warriors and weapons into enemy territory to combat the tumor from within. The most promising immune stimulators are those activating and sustaining Th1 responses, but even if potent effects were seen in preclinical models, many clinical trials failed to show objective responses in cancer patients. However, with new tools to control ongoing immunosuppression in cancer patients, immunostimulatory gene therapy is now emerging as an interesting option. In parallel, oncolytic viruses have been shown to be safe in patients. To prolong immune stimulation and to increase efficacy, these two fields are now merging and oncolytic viruses are armed with immunostimulatory transgenes. These novel agents are racing towards approval as established cancer immunotherapeutics.

Show MeSH
Related in: MedlinePlus