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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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Related in: MedlinePlus

T cells are activated via interactions with antigen presenting cells such as dendritic cells (DCs). When DCs mature they upregulate major histocompatibility complex (MHC) and costimulatory molecules. The T cell recognizing peptides presented by the DC will bind to the DC and receive costimulation. Activated T cells, in turn, express CD40L, which will further stimulate the DCs to increase costimulatory molecules and release cytokines. As an auto-control of immune stimulation, the T cells also express molecules that hamper further activation. For example, PD-1 is upregulated on T cells post activation and if PD-L1 cells are present, the T cells will receive negative signals to restrain activation. Likewise, CTLA-4 will compete with CD28 on binding to the costimulators of the B7 family. However, while CD28 signaling provides costimulation of the T cell, CTLA-4 will block activation. However, the exact mechanism of CTLA-4 is debated.
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viruses-07-02899-f002: T cells are activated via interactions with antigen presenting cells such as dendritic cells (DCs). When DCs mature they upregulate major histocompatibility complex (MHC) and costimulatory molecules. The T cell recognizing peptides presented by the DC will bind to the DC and receive costimulation. Activated T cells, in turn, express CD40L, which will further stimulate the DCs to increase costimulatory molecules and release cytokines. As an auto-control of immune stimulation, the T cells also express molecules that hamper further activation. For example, PD-1 is upregulated on T cells post activation and if PD-L1 cells are present, the T cells will receive negative signals to restrain activation. Likewise, CTLA-4 will compete with CD28 on binding to the costimulators of the B7 family. However, while CD28 signaling provides costimulation of the T cell, CTLA-4 will block activation. However, the exact mechanism of CTLA-4 is debated.

Mentions: Th1 responses are mediated via the activation of antigen presenting cells such as DCs. Immature DCs have a high capacity to engulf cell debris and apoptotic cells. Immature DCs can present antigens to T lymphocytes via both major histocompatibility complex (MHC)-I and II, but with low levels of costimulation and no cytokine production the T lymphocytes will be tolerized instead of activated against the presented antigens. In normal, healthy, tissue immature DCs play an important role in maintaining tolerance to our self-tissue and preventing autoimmune reactions. DCs are activated upon danger signaling via different receptors such as Toll-like receptors (TLRs) that recognize pathogen-associated molecular patterns (PAMPs) and receptors that recognize proteins expressed upon danger such as CD40, CD70 and OX40L [21]. For example, adenoviruses can stimulate plasmacytoid DCs via TLR9 to elicit type I interferon (IFN) responses [22]. It is now known that adenoviruses can stimulate multiple TLRs and unknown cytosolic receptors in DCs to elicit robust anti-viral responses [23]. TLR stimulation can be potentiated with stimulation of other receptors such as CD40 [24]. CD40 is stimulated via its ligand (CD40L), which is rapidly expressed in stressed tissues and is one of the most potent DC activators. Upon activation, the DC differentiates into a mature phenotype that is less likely to engulf antigens but instead increases the expression of MHC-I and II costimulatory molecules and begins to produce cytokines including IL12, which promotes Th1 and blocks Th2 induction (Figure 2). DCs interact with CD4+ Th lymphocytes via the binding of MHC-II to the T cell receptor (TcR) and by a number of costimulatory molecules to induce their production of IL2 and CD40L. CD40L on the lymphocytes in turn stimulates the DCs to maintain the Th1 response and further upregulate costimulatory molecules. The fully licensed DC presents antigens to CD8+ T lymphocytes via MHC-I and a wide range of costimulatory molecules and cytokines. These act together with IL2 from Th lymphocytes to increase the cytotoxic capacity and expand the CD8+ T lymphocytes to large clones of antigen-directed CTLs that can seek and destroy their target cells [21].


Immunostimulatory Gene Therapy Using Oncolytic Viruses as Vehicles.

Loskog A - Viruses (2015)

T cells are activated via interactions with antigen presenting cells such as dendritic cells (DCs). When DCs mature they upregulate major histocompatibility complex (MHC) and costimulatory molecules. The T cell recognizing peptides presented by the DC will bind to the DC and receive costimulation. Activated T cells, in turn, express CD40L, which will further stimulate the DCs to increase costimulatory molecules and release cytokines. As an auto-control of immune stimulation, the T cells also express molecules that hamper further activation. For example, PD-1 is upregulated on T cells post activation and if PD-L1 cells are present, the T cells will receive negative signals to restrain activation. Likewise, CTLA-4 will compete with CD28 on binding to the costimulators of the B7 family. However, while CD28 signaling provides costimulation of the T cell, CTLA-4 will block activation. However, the exact mechanism of CTLA-4 is debated.
© Copyright Policy
Related In: Results  -  Collection

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

viruses-07-02899-f002: T cells are activated via interactions with antigen presenting cells such as dendritic cells (DCs). When DCs mature they upregulate major histocompatibility complex (MHC) and costimulatory molecules. The T cell recognizing peptides presented by the DC will bind to the DC and receive costimulation. Activated T cells, in turn, express CD40L, which will further stimulate the DCs to increase costimulatory molecules and release cytokines. As an auto-control of immune stimulation, the T cells also express molecules that hamper further activation. For example, PD-1 is upregulated on T cells post activation and if PD-L1 cells are present, the T cells will receive negative signals to restrain activation. Likewise, CTLA-4 will compete with CD28 on binding to the costimulators of the B7 family. However, while CD28 signaling provides costimulation of the T cell, CTLA-4 will block activation. However, the exact mechanism of CTLA-4 is debated.
Mentions: Th1 responses are mediated via the activation of antigen presenting cells such as DCs. Immature DCs have a high capacity to engulf cell debris and apoptotic cells. Immature DCs can present antigens to T lymphocytes via both major histocompatibility complex (MHC)-I and II, but with low levels of costimulation and no cytokine production the T lymphocytes will be tolerized instead of activated against the presented antigens. In normal, healthy, tissue immature DCs play an important role in maintaining tolerance to our self-tissue and preventing autoimmune reactions. DCs are activated upon danger signaling via different receptors such as Toll-like receptors (TLRs) that recognize pathogen-associated molecular patterns (PAMPs) and receptors that recognize proteins expressed upon danger such as CD40, CD70 and OX40L [21]. For example, adenoviruses can stimulate plasmacytoid DCs via TLR9 to elicit type I interferon (IFN) responses [22]. It is now known that adenoviruses can stimulate multiple TLRs and unknown cytosolic receptors in DCs to elicit robust anti-viral responses [23]. TLR stimulation can be potentiated with stimulation of other receptors such as CD40 [24]. CD40 is stimulated via its ligand (CD40L), which is rapidly expressed in stressed tissues and is one of the most potent DC activators. Upon activation, the DC differentiates into a mature phenotype that is less likely to engulf antigens but instead increases the expression of MHC-I and II costimulatory molecules and begins to produce cytokines including IL12, which promotes Th1 and blocks Th2 induction (Figure 2). DCs interact with CD4+ Th lymphocytes via the binding of MHC-II to the T cell receptor (TcR) and by a number of costimulatory molecules to induce their production of IL2 and CD40L. CD40L on the lymphocytes in turn stimulates the DCs to maintain the Th1 response and further upregulate costimulatory molecules. The fully licensed DC presents antigens to CD8+ T lymphocytes via MHC-I and a wide range of costimulatory molecules and cytokines. These act together with IL2 from Th lymphocytes to increase the cytotoxic capacity and expand the CD8+ T lymphocytes to large clones of antigen-directed CTLs that can seek and destroy their target cells [21].

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