The Experts below are selected from a list of 6219 Experts worldwide ranked by ideXlab platform
Richard Vile - One of the best experts on this subject based on the ideXlab platform.
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Cytokine-enhanced intravenous oncolytic Virotherapy
The Lancet, 2014Co-Authors: O Donnelly, Timothy Kottke, Richard Vile, Jill Thompson, Elizabeth Ilett, Alan MelcherAbstract:Abstract Background Oncolytic viruses are emerging as promising cancer therapies; a key challenge in their use is delivery of virus to tumour targets in the face of host immunity. In a recent translational clinical study we found that intravenously administered reovirus successfully reaches liver tumours, despite patients all having high concentrations of neutralising anti-reovirus antibodies. Functional virus was recoverable from several white-cell subsets, suggesting that systemically administered virus evades neutralisation by close cell-association (hitch-hiking). We hypothesised that this occurrence could be manipulated to enhance Virotherapy by expanding the numbers of carrier cells in the circulation before viral administration. Methods We used immune competent mice (C57BL/6) that had been vaccinated with reovirus, or phosphate buffered saline (PBS) control, before establishing syngeneic melanoma (B16-Ova) tumours on their flank. Mice were then treated with one of three cytokines—interleukin 2, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF)—or PBS as control, for 3 days, either before or after Virotherapy (reovirus) or PBS as control therapy. Unvaccinated mice were also tested with this regimen. Tumours were then measured daily or harvested for correlative analyses. Mice were humanely killed when tumours reached 1 cm in any dimension. Eight mice were used in each treatment group and experiments were repeated at least twice to ensure consistency of the findings. Findings Treatment with GM-CSF enhanced the number of circulating granulocytes, and enhanced macrophage infiltration into tumours. When reovirus-immune mice were treated with GM-CSF before Virotherapy with reovirus, tumours regressed in all mice and were undetectable 60 days later; but reovirus-immune mice treated with either interleukin 2 or G-CSF before Virotherapy, or treated with GM-CSF alone, all developed tumours that necessitated euthanasia. Moreover the combination of GM-CSF and reovirus was only effective if GM-CSF was administered before reovirus. The efficacy of GM-CSF plus reovirus was considerably diminished in unvaccinated reovirus-naive mice, but was restored if three cycles of GM-CSF plus reovirus were administered, suggesting that in this regimen anti-Rep antibodies contributed to the efficacy of therapy. Interpretation We found that oncolytic Virotherapy with reovirus is enhanced by vaccinating mice against the virus and pretreatment with GM-CSF. Further in-vivo experiments, and associated in-vitro assays, are underway to characterise the mechanism involved. Pragmatically these data suggest a novel method for enhancing oncolytic Virotherapy that can be readily implemented because both reovirus and GM-CSF are used clinically; accordingly a translational clinical trial protocol is being developed to explore this possibility further. Funding UK Medical Research Council, Royal Society of Medicine.
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systemic combination Virotherapy for melanoma with tumor antigen expressing vesicular stomatitis virus and adoptive t cell transfer
Cancer Research, 2012Co-Authors: Diana Rommelfanger, Rosa Maria Diaz, Timothy Kottke, Phonphimon Wongthida, Jill Thompson, Karen M. Kaluza, Richard VileAbstract:Oncolytic Virotherapy offers the potential to treat tumors both as a single agent and in combination with traditional modalities such as chemotherapy and radiotherapy. Here we describe an effective, fully systemic treatment regimen, which combines Virotherapy, acting essentially as an adjuvant immunotherapy, with adoptive cell transfer (ACT). The combination of ACT with systemic administration of a vesicular stomatitis virus (VSV) engineered to express the endogenous melanocyte antigen glycoprotein 100 (gp100) resulted in regression of established melanomas and generation of antitumor immunity. Tumor response was associated with in vivo T-cell persistence and activation as well as treatment-related vitiligo. However, in a proportion of treated mice, initial tumor regressions were followed by recurrences. Therapy was further enhanced by targeting an additional tumor antigen with the VSV-antigen + ACT combination strategy, leading to sustained response in 100% of mice. Together, our findings suggest that systemic Virotherapy combined with antigen-expressing VSV could be used to support and enhance clinical immunotherapy protocols with adoptive T-cell transfer, which are already used in the clinic. Cancer Res; 72(18); 4753–64. ©2012 AACR .
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oncolytic immunoVirotherapy for melanoma using vesicular stomatitis virus
Cancer Research, 2007Co-Authors: Rosa Maria Diaz, Feorillo Galivo, Timothy Kottke, Phonphimon Wongthida, Mikael Valdes, Richard Vile, Jill Thompson, Jian Qiao, Glen N. BarberAbstract:Relatively little attention has been paid to the role of Virotherapy in promoting antitumor immune responses. Here, we show that CD8+ T cells are critical for the efficacy of intratumoral vesicular stomatitis virus Virotherapy and are induced against both virally encoded and tumor-associated immunodominant epitopes. We tested three separate immune interventions to increase the frequency/activity of activated antitumoral T cells. Depletion of Treg had a negative therapeutic effect because it relieved suppression of the antiviral immune response, leading to early viral clearance. In contrast, increasing the circulating levels of tumor antigen–specific T cells using adoptive T cell transfer therapy, in combination with intratumoral Virotherapy, generated significantly improved therapy over either adoptive therapy or Virotherapy alone. Moreover, the incorporation of a tumor-associated antigen within the oncolytic vesicular stomatitis virus increased the levels of activation of naive T cells against the antigen, which translated into increased antitumor therapy. Therefore, our results show that strategies which enhance immune activation against tumor-associated antigens can also be used to enhance the efficacy of Virotherapy. [Cancer Res 2007;67(6):2840–7]
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oncolytic immunoVirotherapy for melanoma using vesicular stomatitis virus
Cancer Research, 2007Co-Authors: Rosa Maria Diaz, Feorillo Galivo, Timothy Kottke, Phonphimon Wongthida, Mikael Valdes, Richard Vile, Jill Thompson, Jian Qiao, Glen N. BarberAbstract:Relatively little attention has been paid to the role of Virotherapy in promoting antitumor immune responses. Here, we show that CD8+ T cells are critical for the efficacy of intratumoral vesicular stomatitis virus Virotherapy and are induced against both virally encoded and tumor-associated immunodominant epitopes. We tested three separate immune interventions to increase the frequency/activity of activated antitumoral T cells. Depletion of Treg had a negative therapeutic effect because it relieved suppression of the antiviral immune response, leading to early viral clearance. In contrast, increasing the circulating levels of tumor antigen-specific T cells using adoptive T cell transfer therapy, in combination with intratumoral Virotherapy, generated significantly improved therapy over either adoptive therapy or Virotherapy alone. Moreover, the incorporation of a tumor-associated antigen within the oncolytic vesicular stomatitis virus increased the levels of activation of naive T cells against the antigen, which translated into increased antitumor therapy. Therefore, our results show that strategies which enhance immune activation against tumor-associated antigens can also be used to enhance the efficacy of Virotherapy.
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56. The Efficacy of Replicating Virotherapy for Tumors Involves a Complex Equilibrium between Virus, Tumor and the Immune System
Molecular Therapy, 2006Co-Authors: Rosa Maria Diaz, Feorillo Galivo, Timothy Kottke, Jill Thompson, Jian Qiao, Glen N. Barber, John C. Bell, Richard VileAbstract:Killing of tumor cells by replicating oncolytic viruses should provide an abundant source of tumor antigens for cross priming of host immune cells. However, anti-viral immune responses will also be induced. Therefore, it is unclear whether the local killing of tumors by oncolytic viruses will be of immunotherapeutic benefit, or hindrance, to the generation of effective anti tumor immunity. We investigated where the equilibrium between viral replication, tumor cell killing and immune reactivity (to both tumor and viral antigens) lies when tumors are undergoing effective oncolytic Virotherapy. Using a model in which direct intratumoral injection of established B16ova melanomas with replicating Vesicular Stomatitis Virus cures about 50% of C57BL/6 immunocompetent mice (n=8-10), extensive anti viral immune responses were generated. However, using ELISPOT, intracellular cytokines and in vivo CFSE T cell proliferation assays, we observed that intratumoral Virotherapy can indeed prime naive T cells against a defined tumor antigen. These data suggest that additional approaches designed to increase the frequency of activated T cells against the tumor would increase the efficiency of oncolytic Virotherapy. Therefore, we combined oncolytic Virotherapy with either depletion of CD4+CD25+ regulatory T cells or with adoptive transfer of activated T cells specific for a tumor antigen. We observed decreased therapy in the absence of Treg, associated with a more rapid clearance of virus replication in the treated tumor. In contrast, ongoing local Virotherapy increases the attraction of activated T cells to the tumor site by over 4 fold relative to control tumors, translating into significant improvement in therapy of established disease over either Virotherapy or adoptive T cell transfer therapy, alone.
Earl E. Henderson - One of the best experts on this subject based on the ideXlab platform.
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Progress in oncolytic Virotherapy for the treatment of thyroid malignant neoplasm
Journal of Experimental & Clinical Cancer Research, 2014Co-Authors: Mingxu Guan, Gaetano Romano, Roberta Coroniti, Earl E. HendersonAbstract:Thyroid malignant neoplasm develops from follicular or parafollicular thyroid cells. A higher proportion of anaplastic thyroid cancer has an adverse prognosis. New drugs are being used in clinical treatment. However, for advanced thyroid malignant neoplasm such as anaplastic thyroid carcinoma, the major impediment to successful control of the disease is the absence of effective therapies. Oncolytic Virotherapy has significantly progressed as therapeutics in recent years. The advance is that oncolytic viruses can be designed with biological specificity to infect, replicate and lyse tumor cells. Significant advances in Virotherapy have being achieved to improve the accessibility, safety and efficacy of the treatment. Therefore, it is necessary to summarize and bring together the main areas covered by these investigations for the Virotherapy of thyroid malignant neoplasm. We provide an overview of the progress in Virotherapy research and clinical trials, which employ Virotherapy for thyroid malignant neoplasm as well as the future prospect for Virotherapy of thyroid malignant neoplasms.
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Progress in oncolytic Virotherapy for treatment of thyroid malignant neoplasm
Journal of Experimental & Clinical Cancer Research, 2014Co-Authors: Mingxu Guan, Gaetano Romano, Roberta Coroniti, Earl E. HendersonAbstract:Thyroid malignant neoplasm develops from follicular or parafollicular thyroid cells. A higher proportion of anaplastic thyroid cancer has an adverse prognosis. New drugs are being used in clinical treatment. However, for advanced thyroid malignant neoplasm such as anaplastic thyroid carcinoma, the major impediment to successful control of the disease is the absence of effective therapies. Oncolytic Virotherapy has significantly progressed as therapeutics in recent years. The advance is that oncolytic viruses can be designed with biological specificity to infect, replicate and lyse tumor cells. Significant advances in Virotherapy have being achieved to improve the accessibility, safety and efficacy of the treatment. Therefore, it is necessary to summarize and bring together the main areas covered by these investigations for the Virotherapy of thyroid malignant neoplasm. We provide an overview of the progress in Virotherapy research and clinical trials, which employ Virotherapy for thyroid malignant neoplasm as well as the future prospect for Virotherapy of thyroid malignant neoplasms.
Rosa Maria Diaz - One of the best experts on this subject based on the ideXlab platform.
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systemic combination Virotherapy for melanoma with tumor antigen expressing vesicular stomatitis virus and adoptive t cell transfer
Cancer Research, 2012Co-Authors: Diana Rommelfanger, Rosa Maria Diaz, Timothy Kottke, Phonphimon Wongthida, Jill Thompson, Karen M. Kaluza, Richard VileAbstract:Oncolytic Virotherapy offers the potential to treat tumors both as a single agent and in combination with traditional modalities such as chemotherapy and radiotherapy. Here we describe an effective, fully systemic treatment regimen, which combines Virotherapy, acting essentially as an adjuvant immunotherapy, with adoptive cell transfer (ACT). The combination of ACT with systemic administration of a vesicular stomatitis virus (VSV) engineered to express the endogenous melanocyte antigen glycoprotein 100 (gp100) resulted in regression of established melanomas and generation of antitumor immunity. Tumor response was associated with in vivo T-cell persistence and activation as well as treatment-related vitiligo. However, in a proportion of treated mice, initial tumor regressions were followed by recurrences. Therapy was further enhanced by targeting an additional tumor antigen with the VSV-antigen + ACT combination strategy, leading to sustained response in 100% of mice. Together, our findings suggest that systemic Virotherapy combined with antigen-expressing VSV could be used to support and enhance clinical immunotherapy protocols with adoptive T-cell transfer, which are already used in the clinic. Cancer Res; 72(18); 4753–64. ©2012 AACR .
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oncolytic immunoVirotherapy for melanoma using vesicular stomatitis virus
Cancer Research, 2007Co-Authors: Rosa Maria Diaz, Feorillo Galivo, Timothy Kottke, Phonphimon Wongthida, Mikael Valdes, Richard Vile, Jill Thompson, Jian Qiao, Glen N. BarberAbstract:Relatively little attention has been paid to the role of Virotherapy in promoting antitumor immune responses. Here, we show that CD8+ T cells are critical for the efficacy of intratumoral vesicular stomatitis virus Virotherapy and are induced against both virally encoded and tumor-associated immunodominant epitopes. We tested three separate immune interventions to increase the frequency/activity of activated antitumoral T cells. Depletion of Treg had a negative therapeutic effect because it relieved suppression of the antiviral immune response, leading to early viral clearance. In contrast, increasing the circulating levels of tumor antigen–specific T cells using adoptive T cell transfer therapy, in combination with intratumoral Virotherapy, generated significantly improved therapy over either adoptive therapy or Virotherapy alone. Moreover, the incorporation of a tumor-associated antigen within the oncolytic vesicular stomatitis virus increased the levels of activation of naive T cells against the antigen, which translated into increased antitumor therapy. Therefore, our results show that strategies which enhance immune activation against tumor-associated antigens can also be used to enhance the efficacy of Virotherapy. [Cancer Res 2007;67(6):2840–7]
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oncolytic immunoVirotherapy for melanoma using vesicular stomatitis virus
Cancer Research, 2007Co-Authors: Rosa Maria Diaz, Feorillo Galivo, Timothy Kottke, Phonphimon Wongthida, Mikael Valdes, Richard Vile, Jill Thompson, Jian Qiao, Glen N. BarberAbstract:Relatively little attention has been paid to the role of Virotherapy in promoting antitumor immune responses. Here, we show that CD8+ T cells are critical for the efficacy of intratumoral vesicular stomatitis virus Virotherapy and are induced against both virally encoded and tumor-associated immunodominant epitopes. We tested three separate immune interventions to increase the frequency/activity of activated antitumoral T cells. Depletion of Treg had a negative therapeutic effect because it relieved suppression of the antiviral immune response, leading to early viral clearance. In contrast, increasing the circulating levels of tumor antigen-specific T cells using adoptive T cell transfer therapy, in combination with intratumoral Virotherapy, generated significantly improved therapy over either adoptive therapy or Virotherapy alone. Moreover, the incorporation of a tumor-associated antigen within the oncolytic vesicular stomatitis virus increased the levels of activation of naive T cells against the antigen, which translated into increased antitumor therapy. Therefore, our results show that strategies which enhance immune activation against tumor-associated antigens can also be used to enhance the efficacy of Virotherapy.
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56. The Efficacy of Replicating Virotherapy for Tumors Involves a Complex Equilibrium between Virus, Tumor and the Immune System
Molecular Therapy, 2006Co-Authors: Rosa Maria Diaz, Feorillo Galivo, Timothy Kottke, Jill Thompson, Jian Qiao, Glen N. Barber, John C. Bell, Richard VileAbstract:Killing of tumor cells by replicating oncolytic viruses should provide an abundant source of tumor antigens for cross priming of host immune cells. However, anti-viral immune responses will also be induced. Therefore, it is unclear whether the local killing of tumors by oncolytic viruses will be of immunotherapeutic benefit, or hindrance, to the generation of effective anti tumor immunity. We investigated where the equilibrium between viral replication, tumor cell killing and immune reactivity (to both tumor and viral antigens) lies when tumors are undergoing effective oncolytic Virotherapy. Using a model in which direct intratumoral injection of established B16ova melanomas with replicating Vesicular Stomatitis Virus cures about 50% of C57BL/6 immunocompetent mice (n=8-10), extensive anti viral immune responses were generated. However, using ELISPOT, intracellular cytokines and in vivo CFSE T cell proliferation assays, we observed that intratumoral Virotherapy can indeed prime naive T cells against a defined tumor antigen. These data suggest that additional approaches designed to increase the frequency of activated T cells against the tumor would increase the efficiency of oncolytic Virotherapy. Therefore, we combined oncolytic Virotherapy with either depletion of CD4+CD25+ regulatory T cells or with adoptive transfer of activated T cells specific for a tumor antigen. We observed decreased therapy in the absence of Treg, associated with a more rapid clearance of virus replication in the treated tumor. In contrast, ongoing local Virotherapy increases the attraction of activated T cells to the tumor site by over 4 fold relative to control tumors, translating into significant improvement in therapy of established disease over either Virotherapy or adoptive T cell transfer therapy, alone.
Mingxu Guan - One of the best experts on this subject based on the ideXlab platform.
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Progress in oncolytic Virotherapy for the treatment of thyroid malignant neoplasm
Journal of Experimental & Clinical Cancer Research, 2014Co-Authors: Mingxu Guan, Gaetano Romano, Roberta Coroniti, Earl E. HendersonAbstract:Thyroid malignant neoplasm develops from follicular or parafollicular thyroid cells. A higher proportion of anaplastic thyroid cancer has an adverse prognosis. New drugs are being used in clinical treatment. However, for advanced thyroid malignant neoplasm such as anaplastic thyroid carcinoma, the major impediment to successful control of the disease is the absence of effective therapies. Oncolytic Virotherapy has significantly progressed as therapeutics in recent years. The advance is that oncolytic viruses can be designed with biological specificity to infect, replicate and lyse tumor cells. Significant advances in Virotherapy have being achieved to improve the accessibility, safety and efficacy of the treatment. Therefore, it is necessary to summarize and bring together the main areas covered by these investigations for the Virotherapy of thyroid malignant neoplasm. We provide an overview of the progress in Virotherapy research and clinical trials, which employ Virotherapy for thyroid malignant neoplasm as well as the future prospect for Virotherapy of thyroid malignant neoplasms.
-
Progress in oncolytic Virotherapy for treatment of thyroid malignant neoplasm
Journal of Experimental & Clinical Cancer Research, 2014Co-Authors: Mingxu Guan, Gaetano Romano, Roberta Coroniti, Earl E. HendersonAbstract:Thyroid malignant neoplasm develops from follicular or parafollicular thyroid cells. A higher proportion of anaplastic thyroid cancer has an adverse prognosis. New drugs are being used in clinical treatment. However, for advanced thyroid malignant neoplasm such as anaplastic thyroid carcinoma, the major impediment to successful control of the disease is the absence of effective therapies. Oncolytic Virotherapy has significantly progressed as therapeutics in recent years. The advance is that oncolytic viruses can be designed with biological specificity to infect, replicate and lyse tumor cells. Significant advances in Virotherapy have being achieved to improve the accessibility, safety and efficacy of the treatment. Therefore, it is necessary to summarize and bring together the main areas covered by these investigations for the Virotherapy of thyroid malignant neoplasm. We provide an overview of the progress in Virotherapy research and clinical trials, which employ Virotherapy for thyroid malignant neoplasm as well as the future prospect for Virotherapy of thyroid malignant neoplasms.
Timothy Kottke - One of the best experts on this subject based on the ideXlab platform.
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Cytokine-enhanced intravenous oncolytic Virotherapy
The Lancet, 2014Co-Authors: O Donnelly, Timothy Kottke, Richard Vile, Jill Thompson, Elizabeth Ilett, Alan MelcherAbstract:Abstract Background Oncolytic viruses are emerging as promising cancer therapies; a key challenge in their use is delivery of virus to tumour targets in the face of host immunity. In a recent translational clinical study we found that intravenously administered reovirus successfully reaches liver tumours, despite patients all having high concentrations of neutralising anti-reovirus antibodies. Functional virus was recoverable from several white-cell subsets, suggesting that systemically administered virus evades neutralisation by close cell-association (hitch-hiking). We hypothesised that this occurrence could be manipulated to enhance Virotherapy by expanding the numbers of carrier cells in the circulation before viral administration. Methods We used immune competent mice (C57BL/6) that had been vaccinated with reovirus, or phosphate buffered saline (PBS) control, before establishing syngeneic melanoma (B16-Ova) tumours on their flank. Mice were then treated with one of three cytokines—interleukin 2, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF)—or PBS as control, for 3 days, either before or after Virotherapy (reovirus) or PBS as control therapy. Unvaccinated mice were also tested with this regimen. Tumours were then measured daily or harvested for correlative analyses. Mice were humanely killed when tumours reached 1 cm in any dimension. Eight mice were used in each treatment group and experiments were repeated at least twice to ensure consistency of the findings. Findings Treatment with GM-CSF enhanced the number of circulating granulocytes, and enhanced macrophage infiltration into tumours. When reovirus-immune mice were treated with GM-CSF before Virotherapy with reovirus, tumours regressed in all mice and were undetectable 60 days later; but reovirus-immune mice treated with either interleukin 2 or G-CSF before Virotherapy, or treated with GM-CSF alone, all developed tumours that necessitated euthanasia. Moreover the combination of GM-CSF and reovirus was only effective if GM-CSF was administered before reovirus. The efficacy of GM-CSF plus reovirus was considerably diminished in unvaccinated reovirus-naive mice, but was restored if three cycles of GM-CSF plus reovirus were administered, suggesting that in this regimen anti-Rep antibodies contributed to the efficacy of therapy. Interpretation We found that oncolytic Virotherapy with reovirus is enhanced by vaccinating mice against the virus and pretreatment with GM-CSF. Further in-vivo experiments, and associated in-vitro assays, are underway to characterise the mechanism involved. Pragmatically these data suggest a novel method for enhancing oncolytic Virotherapy that can be readily implemented because both reovirus and GM-CSF are used clinically; accordingly a translational clinical trial protocol is being developed to explore this possibility further. Funding UK Medical Research Council, Royal Society of Medicine.
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systemic combination Virotherapy for melanoma with tumor antigen expressing vesicular stomatitis virus and adoptive t cell transfer
Cancer Research, 2012Co-Authors: Diana Rommelfanger, Rosa Maria Diaz, Timothy Kottke, Phonphimon Wongthida, Jill Thompson, Karen M. Kaluza, Richard VileAbstract:Oncolytic Virotherapy offers the potential to treat tumors both as a single agent and in combination with traditional modalities such as chemotherapy and radiotherapy. Here we describe an effective, fully systemic treatment regimen, which combines Virotherapy, acting essentially as an adjuvant immunotherapy, with adoptive cell transfer (ACT). The combination of ACT with systemic administration of a vesicular stomatitis virus (VSV) engineered to express the endogenous melanocyte antigen glycoprotein 100 (gp100) resulted in regression of established melanomas and generation of antitumor immunity. Tumor response was associated with in vivo T-cell persistence and activation as well as treatment-related vitiligo. However, in a proportion of treated mice, initial tumor regressions were followed by recurrences. Therapy was further enhanced by targeting an additional tumor antigen with the VSV-antigen + ACT combination strategy, leading to sustained response in 100% of mice. Together, our findings suggest that systemic Virotherapy combined with antigen-expressing VSV could be used to support and enhance clinical immunotherapy protocols with adoptive T-cell transfer, which are already used in the clinic. Cancer Res; 72(18); 4753–64. ©2012 AACR .
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oncolytic immunoVirotherapy for melanoma using vesicular stomatitis virus
Cancer Research, 2007Co-Authors: Rosa Maria Diaz, Feorillo Galivo, Timothy Kottke, Phonphimon Wongthida, Mikael Valdes, Richard Vile, Jill Thompson, Jian Qiao, Glen N. BarberAbstract:Relatively little attention has been paid to the role of Virotherapy in promoting antitumor immune responses. Here, we show that CD8+ T cells are critical for the efficacy of intratumoral vesicular stomatitis virus Virotherapy and are induced against both virally encoded and tumor-associated immunodominant epitopes. We tested three separate immune interventions to increase the frequency/activity of activated antitumoral T cells. Depletion of Treg had a negative therapeutic effect because it relieved suppression of the antiviral immune response, leading to early viral clearance. In contrast, increasing the circulating levels of tumor antigen–specific T cells using adoptive T cell transfer therapy, in combination with intratumoral Virotherapy, generated significantly improved therapy over either adoptive therapy or Virotherapy alone. Moreover, the incorporation of a tumor-associated antigen within the oncolytic vesicular stomatitis virus increased the levels of activation of naive T cells against the antigen, which translated into increased antitumor therapy. Therefore, our results show that strategies which enhance immune activation against tumor-associated antigens can also be used to enhance the efficacy of Virotherapy. [Cancer Res 2007;67(6):2840–7]
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oncolytic immunoVirotherapy for melanoma using vesicular stomatitis virus
Cancer Research, 2007Co-Authors: Rosa Maria Diaz, Feorillo Galivo, Timothy Kottke, Phonphimon Wongthida, Mikael Valdes, Richard Vile, Jill Thompson, Jian Qiao, Glen N. BarberAbstract:Relatively little attention has been paid to the role of Virotherapy in promoting antitumor immune responses. Here, we show that CD8+ T cells are critical for the efficacy of intratumoral vesicular stomatitis virus Virotherapy and are induced against both virally encoded and tumor-associated immunodominant epitopes. We tested three separate immune interventions to increase the frequency/activity of activated antitumoral T cells. Depletion of Treg had a negative therapeutic effect because it relieved suppression of the antiviral immune response, leading to early viral clearance. In contrast, increasing the circulating levels of tumor antigen-specific T cells using adoptive T cell transfer therapy, in combination with intratumoral Virotherapy, generated significantly improved therapy over either adoptive therapy or Virotherapy alone. Moreover, the incorporation of a tumor-associated antigen within the oncolytic vesicular stomatitis virus increased the levels of activation of naive T cells against the antigen, which translated into increased antitumor therapy. Therefore, our results show that strategies which enhance immune activation against tumor-associated antigens can also be used to enhance the efficacy of Virotherapy.
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56. The Efficacy of Replicating Virotherapy for Tumors Involves a Complex Equilibrium between Virus, Tumor and the Immune System
Molecular Therapy, 2006Co-Authors: Rosa Maria Diaz, Feorillo Galivo, Timothy Kottke, Jill Thompson, Jian Qiao, Glen N. Barber, John C. Bell, Richard VileAbstract:Killing of tumor cells by replicating oncolytic viruses should provide an abundant source of tumor antigens for cross priming of host immune cells. However, anti-viral immune responses will also be induced. Therefore, it is unclear whether the local killing of tumors by oncolytic viruses will be of immunotherapeutic benefit, or hindrance, to the generation of effective anti tumor immunity. We investigated where the equilibrium between viral replication, tumor cell killing and immune reactivity (to both tumor and viral antigens) lies when tumors are undergoing effective oncolytic Virotherapy. Using a model in which direct intratumoral injection of established B16ova melanomas with replicating Vesicular Stomatitis Virus cures about 50% of C57BL/6 immunocompetent mice (n=8-10), extensive anti viral immune responses were generated. However, using ELISPOT, intracellular cytokines and in vivo CFSE T cell proliferation assays, we observed that intratumoral Virotherapy can indeed prime naive T cells against a defined tumor antigen. These data suggest that additional approaches designed to increase the frequency of activated T cells against the tumor would increase the efficiency of oncolytic Virotherapy. Therefore, we combined oncolytic Virotherapy with either depletion of CD4+CD25+ regulatory T cells or with adoptive transfer of activated T cells specific for a tumor antigen. We observed decreased therapy in the absence of Treg, associated with a more rapid clearance of virus replication in the treated tumor. In contrast, ongoing local Virotherapy increases the attraction of activated T cells to the tumor site by over 4 fold relative to control tumors, translating into significant improvement in therapy of established disease over either Virotherapy or adoptive T cell transfer therapy, alone.
