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Whole Tumor Antigen Vaccines: Where Are We?

Chiang CL, Coukos G, Kandalaft LE - Vaccines (Basel) (2015)

Bottom Line: Unlike defined tumor-derived peptides and proteins, whole tumor lysate therapy is applicable to all patients regardless of their HLA type.DCs are essentially the master regulators of immune response, and are the most potent antigen-presenting cell population for priming and activating naïve T cells to target tumors.We also discuss the different routes of delivering whole tumor antigens to DCs in vivo and activating them with toll-like receptor agonists.

View Article: PubMed Central - PubMed

Affiliation: Ovarian Cancer Research Center, University of Pennsylvania Medical Center, Philadelphia, PA 19104, USA. cheryl_chiang@yahoo.com.

ABSTRACT
With its vast amount of uncharacterized and characterized T cell epitopes available for activating CD4⁺ T helper and CD8⁺ cytotoxic lymphocytes simultaneously, whole tumor antigen represents an attractive alternative source of antigens as compared to tumor-derived peptides and full-length recombinant tumor proteins for dendritic cell (DC)-based immunotherapy. Unlike defined tumor-derived peptides and proteins, whole tumor lysate therapy is applicable to all patients regardless of their HLA type. DCs are essentially the master regulators of immune response, and are the most potent antigen-presenting cell population for priming and activating naïve T cells to target tumors. Because of these unique properties, numerous DC-based immunotherapies have been initiated in the clinics. In this review, we describe the different types of whole tumor antigens that we could use to pulse DCs ex vivo and in vivo. We also discuss the different routes of delivering whole tumor antigens to DCs in vivo and activating them with toll-like receptor agonists.

No MeSH data available.


Related in: MedlinePlus

Four whole tumor lysate preparations currently in use in the clinics. (A) Hypochlorous acid (HOCl) induces rapid necrotic cell death and enhances the immunogenicity of tumor proteins via oxidation. The increased immunogenicity of HOCl-oxidized tumor proteins are due to a number of mechanisms, including specific binding of oxidized proteins to low-density lipprotein (LDL) receptor to activate dendritic cells (DCs), improved degradation of oxidized proteins by proteinases, improved DC antigen processing and presentation via the major histocompatibility (MHC) molecules, and crosspriming of tumor-specific T cells via T cell receptor (TcR). HOCl might also inactivate IL-10 and transforming growth factor (TGF)-β that can inhibit anti-tumor responses and facilitate T regulatory (Treg) cell proliferation; (B) Ultra-violet B (UVB)-irradiation induces apoptotic tumor cell death. This causes the exposure of phosphatidylserine (PS) and translocation of calreticulin (CRT) to facilitate DC uptake and crosspresentation of the apoptotic tumor cells. The release of high mobility box group-1 (HMGB-1) and pentraxin-3 (PTX-3) by late-stage apoptotic tumor cells can stimulate DC maturation and elicit specific anti-tumor T cell responses; (C) Repeated freeze-thaw treatment of tumor cells induces necrotic cell death and cause the release of numerous danger signals such as HMGB-1, heat-shock proteins (HSPs), DNA, RNA and uric acid that stimulate partial DC maturation. Danger signals such as HSPs, HMGB-1 and uric acid could bind to scavenger receptor-A and toll-like receptor (TLR) 4 on DCs to elicit immune responses; (D) Hyperthermia, which is heat-kill treatment of tumor cells, induces necrotic cell death and increased expression of MICA (major histocompatibility class I chain-related; natural killer group 2D [NKG2D] ligand) and MHC Class I to improved natural killer (NK) cell and antigen-specific CD8+ T cell recognition, respectively.
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vaccines-03-00344-f001: Four whole tumor lysate preparations currently in use in the clinics. (A) Hypochlorous acid (HOCl) induces rapid necrotic cell death and enhances the immunogenicity of tumor proteins via oxidation. The increased immunogenicity of HOCl-oxidized tumor proteins are due to a number of mechanisms, including specific binding of oxidized proteins to low-density lipprotein (LDL) receptor to activate dendritic cells (DCs), improved degradation of oxidized proteins by proteinases, improved DC antigen processing and presentation via the major histocompatibility (MHC) molecules, and crosspriming of tumor-specific T cells via T cell receptor (TcR). HOCl might also inactivate IL-10 and transforming growth factor (TGF)-β that can inhibit anti-tumor responses and facilitate T regulatory (Treg) cell proliferation; (B) Ultra-violet B (UVB)-irradiation induces apoptotic tumor cell death. This causes the exposure of phosphatidylserine (PS) and translocation of calreticulin (CRT) to facilitate DC uptake and crosspresentation of the apoptotic tumor cells. The release of high mobility box group-1 (HMGB-1) and pentraxin-3 (PTX-3) by late-stage apoptotic tumor cells can stimulate DC maturation and elicit specific anti-tumor T cell responses; (C) Repeated freeze-thaw treatment of tumor cells induces necrotic cell death and cause the release of numerous danger signals such as HMGB-1, heat-shock proteins (HSPs), DNA, RNA and uric acid that stimulate partial DC maturation. Danger signals such as HSPs, HMGB-1 and uric acid could bind to scavenger receptor-A and toll-like receptor (TLR) 4 on DCs to elicit immune responses; (D) Hyperthermia, which is heat-kill treatment of tumor cells, induces necrotic cell death and increased expression of MICA (major histocompatibility class I chain-related; natural killer group 2D [NKG2D] ligand) and MHC Class I to improved natural killer (NK) cell and antigen-specific CD8+ T cell recognition, respectively.

Mentions: Live tumor cells are shown to produce immunosuppressive cytokines such as IL-10 and TGF-β to hinder anti-tumor T cell responses and promote T regulatory (Treg) cell functions [35]. TGF-β could also inhibit DC differentiation [36,37] and NK cell functions [38]. Therefore, a whole tumor lysate preparation that simultaneously induces an immunogenic cell death and inactivates immunosuppressive cytokine production from the tumor cells would be highly desirable. In a small-scale phase I recurrent ovarian cancer clinical trial at the University of Pennsylvania, we used hypochlorous acid (HOCl) to induce primary necrosis in the tumor cells as well as increase their immunogenicity for DC uptake and processing [1,39,40]. We optimized this approach in a preclinical mouse ID8 ovarian tumor model by comparing the efficacy of DCs loaded with three different whole tumor lysate preparations, i.e., UVB-irradiated tumor lysate, freeze-thawed lysate and HOCl-oxidized whole tumor lysate. We demonstrated that mice treated with bone marrow-derived DCs pulsed with HOCl-oxidized whole tumor cell lysate of ID8 expressing ovalbumin (ID8-ova) had the best tumor control with >60% cure rate [41]. In contrast, mice that were treated with DCs pulsed with freeze-thawed (100%) and UVB-irradiated ID8-ova whole tumor cell lysate (70%), succumbed to tumor growth and ascites formation. The superiority of HOCl-oxidized whole tumor cell lysate preparation could be attributed to the induction of less Treg cells in peripheral blood and absence of serum IL-10 in the vaccinated mice and not in mice treated with other UVB-irradiated or freeze-thawed whole tumor lysate preparations. We translated these findings into a phase I trial by immunizing patients with autologous DCs loaded with autologous whole tumor cell lysate prepared with HOCl-oxidation [41]. Similar to the ID8 mouse ovarian tumor model, we observed that patients who demonstrated strong anti-tumor T cell responses also showed less peripheral Treg cells and reductions of IL-10 in the sera following immunization. In addition, the monocyte-derived DCs loaded with HOCl-oxidized whole tumor cell lysate produced significantly higher IL-12 upon stimulation with LPS and IFN-γ compared to monocyte-derived DCs loaded with UVB-irradiated or freeze-thawed whole tumor cell lysates. As HOCl-oxidation induces necrotic tumor cell death [39], it could also cause the release of numerous danger signals such as DNA, RNA, ATP, uric acid, HMGB1, and HSP from the oxidized tumor cells to increase their immunogenicity and to activate DCs. In addition, numerous HOCl-oxidized biomolecules including proteins, lipids, and glycoproteins could simultaneously engage and activate various scavenger receptors such as LOX-1 [42], CD36, and MARCO, and possibly TLRs present on DCs perhaps leading to higher IL-12 secretion from DCs. Our group and others have shown that ovarian tumors produced IL-10 and TGF-β [43,44], thus it is reasonable to suggest that HOCl-oxidation and not UVB-irradiation or repeat freeze-thaw cycles might have helped to inactivate these suppressive cytokines in the whole tumor cell lysate. Figure 1 demonstrates the current whole tumor lysate preparations used in clinics.


Whole Tumor Antigen Vaccines: Where Are We?

Chiang CL, Coukos G, Kandalaft LE - Vaccines (Basel) (2015)

Four whole tumor lysate preparations currently in use in the clinics. (A) Hypochlorous acid (HOCl) induces rapid necrotic cell death and enhances the immunogenicity of tumor proteins via oxidation. The increased immunogenicity of HOCl-oxidized tumor proteins are due to a number of mechanisms, including specific binding of oxidized proteins to low-density lipprotein (LDL) receptor to activate dendritic cells (DCs), improved degradation of oxidized proteins by proteinases, improved DC antigen processing and presentation via the major histocompatibility (MHC) molecules, and crosspriming of tumor-specific T cells via T cell receptor (TcR). HOCl might also inactivate IL-10 and transforming growth factor (TGF)-β that can inhibit anti-tumor responses and facilitate T regulatory (Treg) cell proliferation; (B) Ultra-violet B (UVB)-irradiation induces apoptotic tumor cell death. This causes the exposure of phosphatidylserine (PS) and translocation of calreticulin (CRT) to facilitate DC uptake and crosspresentation of the apoptotic tumor cells. The release of high mobility box group-1 (HMGB-1) and pentraxin-3 (PTX-3) by late-stage apoptotic tumor cells can stimulate DC maturation and elicit specific anti-tumor T cell responses; (C) Repeated freeze-thaw treatment of tumor cells induces necrotic cell death and cause the release of numerous danger signals such as HMGB-1, heat-shock proteins (HSPs), DNA, RNA and uric acid that stimulate partial DC maturation. Danger signals such as HSPs, HMGB-1 and uric acid could bind to scavenger receptor-A and toll-like receptor (TLR) 4 on DCs to elicit immune responses; (D) Hyperthermia, which is heat-kill treatment of tumor cells, induces necrotic cell death and increased expression of MICA (major histocompatibility class I chain-related; natural killer group 2D [NKG2D] ligand) and MHC Class I to improved natural killer (NK) cell and antigen-specific CD8+ T cell recognition, respectively.
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Related In: Results  -  Collection

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vaccines-03-00344-f001: Four whole tumor lysate preparations currently in use in the clinics. (A) Hypochlorous acid (HOCl) induces rapid necrotic cell death and enhances the immunogenicity of tumor proteins via oxidation. The increased immunogenicity of HOCl-oxidized tumor proteins are due to a number of mechanisms, including specific binding of oxidized proteins to low-density lipprotein (LDL) receptor to activate dendritic cells (DCs), improved degradation of oxidized proteins by proteinases, improved DC antigen processing and presentation via the major histocompatibility (MHC) molecules, and crosspriming of tumor-specific T cells via T cell receptor (TcR). HOCl might also inactivate IL-10 and transforming growth factor (TGF)-β that can inhibit anti-tumor responses and facilitate T regulatory (Treg) cell proliferation; (B) Ultra-violet B (UVB)-irradiation induces apoptotic tumor cell death. This causes the exposure of phosphatidylserine (PS) and translocation of calreticulin (CRT) to facilitate DC uptake and crosspresentation of the apoptotic tumor cells. The release of high mobility box group-1 (HMGB-1) and pentraxin-3 (PTX-3) by late-stage apoptotic tumor cells can stimulate DC maturation and elicit specific anti-tumor T cell responses; (C) Repeated freeze-thaw treatment of tumor cells induces necrotic cell death and cause the release of numerous danger signals such as HMGB-1, heat-shock proteins (HSPs), DNA, RNA and uric acid that stimulate partial DC maturation. Danger signals such as HSPs, HMGB-1 and uric acid could bind to scavenger receptor-A and toll-like receptor (TLR) 4 on DCs to elicit immune responses; (D) Hyperthermia, which is heat-kill treatment of tumor cells, induces necrotic cell death and increased expression of MICA (major histocompatibility class I chain-related; natural killer group 2D [NKG2D] ligand) and MHC Class I to improved natural killer (NK) cell and antigen-specific CD8+ T cell recognition, respectively.
Mentions: Live tumor cells are shown to produce immunosuppressive cytokines such as IL-10 and TGF-β to hinder anti-tumor T cell responses and promote T regulatory (Treg) cell functions [35]. TGF-β could also inhibit DC differentiation [36,37] and NK cell functions [38]. Therefore, a whole tumor lysate preparation that simultaneously induces an immunogenic cell death and inactivates immunosuppressive cytokine production from the tumor cells would be highly desirable. In a small-scale phase I recurrent ovarian cancer clinical trial at the University of Pennsylvania, we used hypochlorous acid (HOCl) to induce primary necrosis in the tumor cells as well as increase their immunogenicity for DC uptake and processing [1,39,40]. We optimized this approach in a preclinical mouse ID8 ovarian tumor model by comparing the efficacy of DCs loaded with three different whole tumor lysate preparations, i.e., UVB-irradiated tumor lysate, freeze-thawed lysate and HOCl-oxidized whole tumor lysate. We demonstrated that mice treated with bone marrow-derived DCs pulsed with HOCl-oxidized whole tumor cell lysate of ID8 expressing ovalbumin (ID8-ova) had the best tumor control with >60% cure rate [41]. In contrast, mice that were treated with DCs pulsed with freeze-thawed (100%) and UVB-irradiated ID8-ova whole tumor cell lysate (70%), succumbed to tumor growth and ascites formation. The superiority of HOCl-oxidized whole tumor cell lysate preparation could be attributed to the induction of less Treg cells in peripheral blood and absence of serum IL-10 in the vaccinated mice and not in mice treated with other UVB-irradiated or freeze-thawed whole tumor lysate preparations. We translated these findings into a phase I trial by immunizing patients with autologous DCs loaded with autologous whole tumor cell lysate prepared with HOCl-oxidation [41]. Similar to the ID8 mouse ovarian tumor model, we observed that patients who demonstrated strong anti-tumor T cell responses also showed less peripheral Treg cells and reductions of IL-10 in the sera following immunization. In addition, the monocyte-derived DCs loaded with HOCl-oxidized whole tumor cell lysate produced significantly higher IL-12 upon stimulation with LPS and IFN-γ compared to monocyte-derived DCs loaded with UVB-irradiated or freeze-thawed whole tumor cell lysates. As HOCl-oxidation induces necrotic tumor cell death [39], it could also cause the release of numerous danger signals such as DNA, RNA, ATP, uric acid, HMGB1, and HSP from the oxidized tumor cells to increase their immunogenicity and to activate DCs. In addition, numerous HOCl-oxidized biomolecules including proteins, lipids, and glycoproteins could simultaneously engage and activate various scavenger receptors such as LOX-1 [42], CD36, and MARCO, and possibly TLRs present on DCs perhaps leading to higher IL-12 secretion from DCs. Our group and others have shown that ovarian tumors produced IL-10 and TGF-β [43,44], thus it is reasonable to suggest that HOCl-oxidation and not UVB-irradiation or repeat freeze-thaw cycles might have helped to inactivate these suppressive cytokines in the whole tumor cell lysate. Figure 1 demonstrates the current whole tumor lysate preparations used in clinics.

Bottom Line: Unlike defined tumor-derived peptides and proteins, whole tumor lysate therapy is applicable to all patients regardless of their HLA type.DCs are essentially the master regulators of immune response, and are the most potent antigen-presenting cell population for priming and activating naïve T cells to target tumors.We also discuss the different routes of delivering whole tumor antigens to DCs in vivo and activating them with toll-like receptor agonists.

View Article: PubMed Central - PubMed

Affiliation: Ovarian Cancer Research Center, University of Pennsylvania Medical Center, Philadelphia, PA 19104, USA. cheryl_chiang@yahoo.com.

ABSTRACT
With its vast amount of uncharacterized and characterized T cell epitopes available for activating CD4⁺ T helper and CD8⁺ cytotoxic lymphocytes simultaneously, whole tumor antigen represents an attractive alternative source of antigens as compared to tumor-derived peptides and full-length recombinant tumor proteins for dendritic cell (DC)-based immunotherapy. Unlike defined tumor-derived peptides and proteins, whole tumor lysate therapy is applicable to all patients regardless of their HLA type. DCs are essentially the master regulators of immune response, and are the most potent antigen-presenting cell population for priming and activating naïve T cells to target tumors. Because of these unique properties, numerous DC-based immunotherapies have been initiated in the clinics. In this review, we describe the different types of whole tumor antigens that we could use to pulse DCs ex vivo and in vivo. We also discuss the different routes of delivering whole tumor antigens to DCs in vivo and activating them with toll-like receptor agonists.

No MeSH data available.


Related in: MedlinePlus