The Experts below are selected from a list of 2814 Experts worldwide ranked by ideXlab platform
Laetitia Fend - One of the best experts on this subject based on the ideXlab platform.
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immune checkpoint blockade immunogenic chemotherapy or ifn α blockade boost the local and abscopal effects of Oncolytic Virotherapy
Cancer Research, 2017Co-Authors: Laetitia Fend, Takahiro Yamazaki, Christelle Remy, Catherine Fahrner, Murielle Gantzer, Virginie Nourtier, Xavier Preville, Eric QuemeneurAbstract:Athough the clinical efficacy of Oncolytic viruses has been demonstrated for local treatment, the ability to induce immune-mediated regression of distant metastases is still poorly documented. We report here that the engineered Oncolytic vaccinia virus VVWR-TK-RR--Fcu1 can induce immunogenic cell death and generate a systemic immune response. Effects on tumor growth and survival was largely driven by CD8+ T cells, and immune cell infiltrate in the tumor could be reprogrammed toward a higher ratio of effector T cells to regulatory CD4+ T cells. The key role of type 1 IFN pathway in Oncolytic Virotherapy was also highlighted, as we observed a strong abscopal response in Ifnar-/- tumors. In this model, single administration of virus directly into the tumors on one flank led to regression in the contralateral flank. Moreover, these effects were further enhanced when Oncolytic treatment was combined with immunogenic chemotherapy or with immune checkpoint blockade. Taken together, our results suggest how to safely improve the efficacy of local Oncolytic Virotherapy in patients whose tumors are characterized by dysregulated IFNα signaling. Cancer Res; 77(15); 4146-57. ©2017 AACR.
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abstract 4563 local and abscopal effects in Oncolytic Virotherapy are boosted by immune checkpoint blockade immunogenic chemotherapy or ifnar blockade
Cancer Research, 2017Co-Authors: Laetitia Fend, Guido Kroemer, Takahiro Yamazaki, Xavier Preville, Eric Quemeneur, Oliver Kepp, Julien Adam, Aurelien Marabelle, Jonathan M Pitt, Laurence ZitvogelAbstract:Athough the clinical efficacy of Oncolytic viruses has been demonstrated for local treatment, the ability to induce immune-mediated regression of distant metastases is still poorly documented. We here report that an engineered Oncolytic Vaccinia Virus, VVWR-TK-RR--Fcu1, is able to induce an immunogenic cell death and thus to generate a systemic immune response. Effect on tumor growth and survival is largely driven by CD8+ T-cells, and we could demonstrate that the immune cell infiltrate in the tumor could be reprogrammed towards a higher ratio of effector T-cells to regulatory CD4+ T-cells. The key role of the type 1-IFN pathway in Oncolytic Virotherapy was also highlighted, and we could show a strong abscopal response in Ifnar-/- tumors. In this model, the single administration of the virus directly into the tumors, on one flank, led to regression in the contralateral flank (i.e. opposite to the virus injection site). Moreover, we observed that these effects are further enhanced when the Oncolytic treatment is combined with either immunogenic chemotherapy such as oxaliplatin, or with immune checkpoint blockers such as anti-PD-1 or anti-CTLA-4. Altogether, these data suggest that local Oncolytic Virotherapy in patients with tumors altered in IFNAR signaling could increase immune-mediated abscopal regression of distant metastases. Citation Format: Laetitia Fend, Takahiro Yamazaki, Xavier Preville, Eric Quemeneur, Oliver Kepp, Julien Adam, Aurelien Marabelle, Jonathan Pitt, Guido Kroemer, Laurence Zitvogel. Local and abscopal effects in Oncolytic Virotherapy are boosted by immune checkpoint blockade, immunogenic chemotherapy, or IFNAR blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4563. doi:10.1158/1538-7445.AM2017-4563
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Oncolytic Virotherapy with an armed vaccinia virus in an orthotopic model of renal carcinoma is associated with modification of the tumor microenvironment
OncoImmunology, 2016Co-Authors: Laetitia Fend, Christelle Remyziller, Johann Foloppe, Juliette Kempf, Sandrine Cochin, Luc Barraud, Nathalie Accart, Philippe Erbs, Sylvie Fournel, Xavier PrevilleAbstract:Oncolytic Virotherapy is an emergent promising therapeutic approach for the treatment of cancer. We have constructed a vaccinia virus (WR strain) deleted for thymidine kinase (TK) and ribonucleotide reductase (RR) genes that expressed the fusion suicide gene FCU1 derived from the yeast cytosine deaminase and uracil phosphoribosyltransferase genes. We evaluated this construct (VV-FCU1) in the orthotopic model of renal carcinoma (RenCa). Systemic administration of VV-FCU1 resulted in orthotopic tumor growth inhibition, despite temporary expression of viral proteins. VV-FCU1 treatment was associated with an infiltration of tumors by CD8+ T lymphocytes and a decrease in the proportion of infiltrating Tregs, thus modifying the ratio of CD8+/CD4+ Treg in favor of CD8+cytotoxic T cells. We demonstrated that VV-FCU1 treatment prolonged survival of animals implanted with RenCa cells in kidney. Depletion of CD8+ T cells abolished the therapeutic effect of VV-FCU1 while depletion of CD4+ T cells enhanced its protective activity. Administration of the prodrug 5-fluorocytosine (5-FC) resulted in a sustained control of tumor growth but did not extend survival. This study shows the importance of CD4+ and CD8+ T cells in vaccinia virus-mediated Oncolytic Virotherapy and suggests that this approach may be evaluated for the treatment of human renal cell carcinoma.
Yu Han - One of the best experts on this subject based on the ideXlab platform.
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mesenchymal stem cells successfully deliver Oncolytic Virotherapy to diffuse intrinsic pontine glioma
Clinical Cancer Research, 2021Co-Authors: Michael Chastkofsky, Katarzyna C Pituch, Hiroaki Katagi, Liliana Ilut, Ting Xiao, Yu Han, Adam M Sonabend, David T Curiel, Markella Zannikou, Erin R BonnerAbstract:Purpose: Diffuse intrinsic pontine glioma (DIPG) is among the deadliest of pediatric brain tumors. Radiotherapy is the standard-of-care treatment for DIPG, but offers only transient relief of symptoms for patients with DIPG without providing significant survival benefit. Oncolytic Virotherapy is an anticancer treatment that has been investigated for treating various types of brain tumors. Experimental Design: Here, we have explored the use of mesenchymal stem cells (MSC) for Oncolytic virus (OV) delivery and evaluated treatment efficacy using preclinical models of DIPG. The survivin promoter drives the conditional replication of OV used in our studies. The efficiency of OV entry into the cells is mediated by fiber modification with seven lysine residues (CRAd.S.pK7). Patients9 samples and cell lines were analyzed for the expression of viral entry proteins and survivin. The ability of MSCs to deliver OV to DIPG was studied in the context of a low dose of irradiation. Results: Our results show that DIPG cells and tumors exhibit robust expression of cell surface proteins and survivin that enable efficient OV entry and replication in DIPG cells. MSCs loaded with OV disseminate within a tumor and release OV throughout the DIPG brainstem xenografts in mice. Administration of OV-loaded MSCs with radiotherapy to mice bearing brainstem DIPG xenografts results in more prolonged survival relative to that conferred by either therapy alone (P Conclusions: Our study supports OV, CRAd.S.pK7, encapsulated within MSCs as a therapeutic strategy that merits further investigation and potential translation for DIPG treatment.
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mscs successfully deliver Oncolytic Virotherapy to diffuse intrinsic pontine glioma
bioRxiv, 2020Co-Authors: Michael Chastkofsky, Katarzyna C Pituch, Hiroaki Katagi, Liliana Ilut, Ting Xiao, Yu Han, Adam M Sonabend, David T Curiel, Erin R BonnerAbstract:Diffuse intrinsic pontine glioma (DIPG) is among the deadliest of pediatric brain tumors. Radiation therapy is the standard of care treatment for DIPG, but offers only transient relief of symptoms for DIPG patients without providing significant survival benefit. Oncolytic Virotherapy (OV) is an anticancer treatment that has been investigated for treating various types of brain tumors. Here, we have explored the use of mesenchymal stem cells (MSC) for OV delivery and evaluated treatment efficacy using preclinical models of DIPG. Our results show that DIPG cells and tumors exhibit robust expression of cell surface proteins that are important for OV entry, and that MSCs loaded with OV disseminate within and release OV throughout the tumor in mice bearing DIPG brainstem xenografts. When combining administration of OV-loaded MSCs with radiotherapy, mice bearing brainstem DIPG xenografts experience a significant survival benefit, relative to that conferred by either therapy alone (p
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mscs successfully deliver Oncolytic Virotherapy to diffuse intrinsic pontine glioma
bioRxiv, 2020Co-Authors: Michael Chastkofsky, Katarzyna C Pituch, Hiroaki Katagi, Liliana Ilut, Ting Xiao, Yu Han, Adam M Sonabend, David T Curiel, Erin R BonnerAbstract:Diffuse intrinsic pontine glioma (DIPG) is among the deadliest of pediatric brain tumors. Radiation therapy is the standard of care treatment for DIPG, but offers only transient relief of symptoms for DIPG patients without providing significant survival benefit. Oncolytic Virotherapy (OV) is an anticancer treatment that has been investigated for treating various types of brain tumors. Here, we have explored the use of mesenchymal stem cells (MSC) for OV delivery and evaluated treatment efficacy using preclinical models of DIPG. Our results show that DIPG cells and tumors exhibit robust expression of cell surface proteins that are important for OV entry, and that MSCs loaded with OV disseminate within and release OV throughout the tumor in mice bearing DIPG brainstem xenografts. When combining administration of OV-loaded MSCs with radiotherapy, mice bearing brainstem DIPG xenografts experience a significant survival benefit, relative to that conferred by either therapy alone (p<0.0001). Our results support further preclinical investigation of cell-based OV therapy with radiation for potential translation in treating DIPG patients.
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a preclinical evaluation of neural stem cell based cell carrier for targeted antiglioma Oncolytic Virotherapy
Journal of the National Cancer Institute, 2013Co-Authors: Atique U Ahmed, Yu Han, Bart Thaci, Alex Tobias, Brenda Auffinger, Lingjiao Zhang, Yu Cheng, Chung Kwon Kim, Catherine Yunis, Nikita G AlexiadesAbstract:Neural stem cells (NSCs) are defined as multipotent progenitor cells that originate from the developing and adult central nervous system (1). NSCs display intrinsic tumor tropism that can be exploited for targeted anticancer drug delivery to invasive and metastatic cancer (2,3). In theory, the tumor-homing property of NSCs offers a substantial advantage over other targeted therapies, such as antibody-directed drug delivery, because of their ability to detect various cues generated by satellite tumor foci and respond to such cues by extravasating through complex tissue microenvironments and migrating to distant diseased areas (4). Glioblastoma multiforme (GBM) is the most common and aggressive primary central nervous system tumor in adults and is characterized by its propensity to infiltrate throughout the brain and cause relapses in patients because of the existence of an aberrant chemo- and radio-resistant glioma stem cell (GSC) population (5). Thus, a true cure for this formidable disease cannot arise from the application of traditional antineoplastic principles; it requires a dynamic agent capable of targeting scattered disease lesions as well as eliminating the tumor-initiating cancer stem cells effectively with minimal disruption of the existing delicate neural architecture (6). Based on this, our lab has extensively evaluated NSCs as a cellular vehicle for the targeted delivery of glioma tropic Oncolytic adenoviral Virotherapy (OV) CRAd-S-pk7 (7–9). We have proposed that by combining NSCs’ unique tumor tropism with the OV’s ability to target chemo- and radio-resistant GSCs (6,10) we may overcome the deficiencies inherent to each approach deployed in isolation and can effectively target GBM. As a proof-of-principle we have previously demonstrated that 1) NSCs can be used as cellular vehicles for the in vivo delivery of an OV to intracranial gliomas (7); 2) intratumoral delivery of NSCs loaded with the CRAd-S-pk7, a glioma-tropic OV regulated by the tumor-specific survivin promoter (7,11), increased median survival by 50% compared with mice treated with OV alone in an orthotopic xenograft model of human glioma (8); and 3) NSCs demonstrated superior therapeutic efficacy when compared with mesenchymal stem cells as a cell carrier for OV in the context of intracranial gliomas (9). Because these previously published results argue in favor of using NSCs as targeted cellular delivery vehicles for antiglioma Oncolytic Virotherapy, we conducted the following critical translational studies to justify its application in a phase I clinical trial for patients with GBM: 1) identified an optimal NSC-based cell carrier for antiglioma Oncolytic Virotherapy; 2) tested the selected NSC-based cell carrier in several diverse and clinically relevant glioma xenograft models; 3) developed a noninvasive imaging protocol to monitor in vivo distribution and migratory activity of NSC-based cell carriers in real time; 4) examined the capacity for the NSC-based cell carrier to deliver antiglioma OV to a distant tumor burden in a glioma xenograft model; and 5) evaluated the therapeutic efficacy of NSC-based Oncolytic Virotherapy in a distance-delivery glioma xenograft model. In this report, we provide a detailed evaluation of two immortalized NSC lines as cell carriers for targeted antiglioma therapy. Our results indicate that HB1.F3.CD, a US Food and Drug Administration–approved NSC line for human clinical trials (NCT01172964) is the most suitable NSC cell carrier for the future application of cell-based OV delivery in the clinical setting. We found that HB1.F3.CD cells can effectively hand off the viral therapeutic payload to distant tumor sites and substantially prolong median survival in diverse orthotopic models of human glioma. Thus, data presented in this study solidify the notion that NSCs can be used as cell carriers for the targeted delivery of antiglioma Oncolytic viruses and serve as the foundation for an investigational new drug application for a human clinical trial involving newly diagnosed and recurrent patients with malignant gliomas.
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pharmacokinetic study of neural stem cell based cell carrier for Oncolytic Virotherapy targeted delivery of the therapeutic payload in an orthotopic brain tumor model
Cancer Gene Therapy, 2012Co-Authors: Bart Thaci, Yu Han, Atique U Ahmed, Ilya V Ulasov, Alex Tobias, Karen S Aboody, Maciej S LesniakAbstract:Oncolytic Virotherapy is a promising novel therapy for glioblastoma that needs to be optimized before introduced to clinic. The targeting of conditionally replicating adenoviruses (CRAds) can be improved by relying on the tumor-tropic properties of neural stem cells (NSCs). Here, we report the characterization of an FDA approved NSC, HB1.F3-CD, as a cell carrier for CRAd-S-pk7, a glioma-tropic Oncolytic adenovirus. We show that NSCs replicate and release infectious CRAd-S-pk7 progeny capable of lysing glioma cell lines. Moreover, ex-vivo-loaded NSCs, injected intracranially in nude mice bearing human glioma xenografts (i) retained their tumor tropism, (ii) continued to replicate CRAd-S-pk7 for more than a week after reaching the tumor site and (iii) successfully handed off CRAd-S-pk7 to glioma cells in vivo. Delivery via carrier cells reduced non-specific adenovirus distribution in the mouse brain. Moreover, we assessed biodistribution of loaded NSCs after intracranial injection in animal models semi-permissive to adenovirus replication, the Syrian hamster and cotton rat. NSCs did not migrate to distant organs and high levels of CRAd-S-pk7 DNA were observed only in the injected hemisphere. In conclusion, this optimized carrier system, with high efficiency of adenovirus delivery and minimal systemic toxicity, poses considerable advantages for anti-glioma Oncolytic Virotherapy.
Takahiro Yamazaki - One of the best experts on this subject based on the ideXlab platform.
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immune checkpoint blockade immunogenic chemotherapy or ifn α blockade boost the local and abscopal effects of Oncolytic Virotherapy
Cancer Research, 2017Co-Authors: Laetitia Fend, Takahiro Yamazaki, Christelle Remy, Catherine Fahrner, Murielle Gantzer, Virginie Nourtier, Xavier Preville, Eric QuemeneurAbstract:Athough the clinical efficacy of Oncolytic viruses has been demonstrated for local treatment, the ability to induce immune-mediated regression of distant metastases is still poorly documented. We report here that the engineered Oncolytic vaccinia virus VVWR-TK-RR--Fcu1 can induce immunogenic cell death and generate a systemic immune response. Effects on tumor growth and survival was largely driven by CD8+ T cells, and immune cell infiltrate in the tumor could be reprogrammed toward a higher ratio of effector T cells to regulatory CD4+ T cells. The key role of type 1 IFN pathway in Oncolytic Virotherapy was also highlighted, as we observed a strong abscopal response in Ifnar-/- tumors. In this model, single administration of virus directly into the tumors on one flank led to regression in the contralateral flank. Moreover, these effects were further enhanced when Oncolytic treatment was combined with immunogenic chemotherapy or with immune checkpoint blockade. Taken together, our results suggest how to safely improve the efficacy of local Oncolytic Virotherapy in patients whose tumors are characterized by dysregulated IFNα signaling. Cancer Res; 77(15); 4146-57. ©2017 AACR.
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abstract 4563 local and abscopal effects in Oncolytic Virotherapy are boosted by immune checkpoint blockade immunogenic chemotherapy or ifnar blockade
Cancer Research, 2017Co-Authors: Laetitia Fend, Guido Kroemer, Takahiro Yamazaki, Xavier Preville, Eric Quemeneur, Oliver Kepp, Julien Adam, Aurelien Marabelle, Jonathan M Pitt, Laurence ZitvogelAbstract:Athough the clinical efficacy of Oncolytic viruses has been demonstrated for local treatment, the ability to induce immune-mediated regression of distant metastases is still poorly documented. We here report that an engineered Oncolytic Vaccinia Virus, VVWR-TK-RR--Fcu1, is able to induce an immunogenic cell death and thus to generate a systemic immune response. Effect on tumor growth and survival is largely driven by CD8+ T-cells, and we could demonstrate that the immune cell infiltrate in the tumor could be reprogrammed towards a higher ratio of effector T-cells to regulatory CD4+ T-cells. The key role of the type 1-IFN pathway in Oncolytic Virotherapy was also highlighted, and we could show a strong abscopal response in Ifnar-/- tumors. In this model, the single administration of the virus directly into the tumors, on one flank, led to regression in the contralateral flank (i.e. opposite to the virus injection site). Moreover, we observed that these effects are further enhanced when the Oncolytic treatment is combined with either immunogenic chemotherapy such as oxaliplatin, or with immune checkpoint blockers such as anti-PD-1 or anti-CTLA-4. Altogether, these data suggest that local Oncolytic Virotherapy in patients with tumors altered in IFNAR signaling could increase immune-mediated abscopal regression of distant metastases. Citation Format: Laetitia Fend, Takahiro Yamazaki, Xavier Preville, Eric Quemeneur, Oliver Kepp, Julien Adam, Aurelien Marabelle, Jonathan Pitt, Guido Kroemer, Laurence Zitvogel. Local and abscopal effects in Oncolytic Virotherapy are boosted by immune checkpoint blockade, immunogenic chemotherapy, or IFNAR blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4563. doi:10.1158/1538-7445.AM2017-4563
Atique U Ahmed - One of the best experts on this subject based on the ideXlab platform.
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a preclinical evaluation of neural stem cell based cell carrier for targeted antiglioma Oncolytic Virotherapy
Journal of the National Cancer Institute, 2013Co-Authors: Atique U Ahmed, Yu Han, Bart Thaci, Alex Tobias, Brenda Auffinger, Lingjiao Zhang, Yu Cheng, Chung Kwon Kim, Catherine Yunis, Nikita G AlexiadesAbstract:Neural stem cells (NSCs) are defined as multipotent progenitor cells that originate from the developing and adult central nervous system (1). NSCs display intrinsic tumor tropism that can be exploited for targeted anticancer drug delivery to invasive and metastatic cancer (2,3). In theory, the tumor-homing property of NSCs offers a substantial advantage over other targeted therapies, such as antibody-directed drug delivery, because of their ability to detect various cues generated by satellite tumor foci and respond to such cues by extravasating through complex tissue microenvironments and migrating to distant diseased areas (4). Glioblastoma multiforme (GBM) is the most common and aggressive primary central nervous system tumor in adults and is characterized by its propensity to infiltrate throughout the brain and cause relapses in patients because of the existence of an aberrant chemo- and radio-resistant glioma stem cell (GSC) population (5). Thus, a true cure for this formidable disease cannot arise from the application of traditional antineoplastic principles; it requires a dynamic agent capable of targeting scattered disease lesions as well as eliminating the tumor-initiating cancer stem cells effectively with minimal disruption of the existing delicate neural architecture (6). Based on this, our lab has extensively evaluated NSCs as a cellular vehicle for the targeted delivery of glioma tropic Oncolytic adenoviral Virotherapy (OV) CRAd-S-pk7 (7–9). We have proposed that by combining NSCs’ unique tumor tropism with the OV’s ability to target chemo- and radio-resistant GSCs (6,10) we may overcome the deficiencies inherent to each approach deployed in isolation and can effectively target GBM. As a proof-of-principle we have previously demonstrated that 1) NSCs can be used as cellular vehicles for the in vivo delivery of an OV to intracranial gliomas (7); 2) intratumoral delivery of NSCs loaded with the CRAd-S-pk7, a glioma-tropic OV regulated by the tumor-specific survivin promoter (7,11), increased median survival by 50% compared with mice treated with OV alone in an orthotopic xenograft model of human glioma (8); and 3) NSCs demonstrated superior therapeutic efficacy when compared with mesenchymal stem cells as a cell carrier for OV in the context of intracranial gliomas (9). Because these previously published results argue in favor of using NSCs as targeted cellular delivery vehicles for antiglioma Oncolytic Virotherapy, we conducted the following critical translational studies to justify its application in a phase I clinical trial for patients with GBM: 1) identified an optimal NSC-based cell carrier for antiglioma Oncolytic Virotherapy; 2) tested the selected NSC-based cell carrier in several diverse and clinically relevant glioma xenograft models; 3) developed a noninvasive imaging protocol to monitor in vivo distribution and migratory activity of NSC-based cell carriers in real time; 4) examined the capacity for the NSC-based cell carrier to deliver antiglioma OV to a distant tumor burden in a glioma xenograft model; and 5) evaluated the therapeutic efficacy of NSC-based Oncolytic Virotherapy in a distance-delivery glioma xenograft model. In this report, we provide a detailed evaluation of two immortalized NSC lines as cell carriers for targeted antiglioma therapy. Our results indicate that HB1.F3.CD, a US Food and Drug Administration–approved NSC line for human clinical trials (NCT01172964) is the most suitable NSC cell carrier for the future application of cell-based OV delivery in the clinical setting. We found that HB1.F3.CD cells can effectively hand off the viral therapeutic payload to distant tumor sites and substantially prolong median survival in diverse orthotopic models of human glioma. Thus, data presented in this study solidify the notion that NSCs can be used as cell carriers for the targeted delivery of antiglioma Oncolytic viruses and serve as the foundation for an investigational new drug application for a human clinical trial involving newly diagnosed and recurrent patients with malignant gliomas.
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pharmacokinetic study of neural stem cell based cell carrier for Oncolytic Virotherapy targeted delivery of the therapeutic payload in an orthotopic brain tumor model
Cancer Gene Therapy, 2012Co-Authors: Bart Thaci, Yu Han, Atique U Ahmed, Ilya V Ulasov, Alex Tobias, Karen S Aboody, Maciej S LesniakAbstract:Oncolytic Virotherapy is a promising novel therapy for glioblastoma that needs to be optimized before introduced to clinic. The targeting of conditionally replicating adenoviruses (CRAds) can be improved by relying on the tumor-tropic properties of neural stem cells (NSCs). Here, we report the characterization of an FDA approved NSC, HB1.F3-CD, as a cell carrier for CRAd-S-pk7, a glioma-tropic Oncolytic adenovirus. We show that NSCs replicate and release infectious CRAd-S-pk7 progeny capable of lysing glioma cell lines. Moreover, ex-vivo-loaded NSCs, injected intracranially in nude mice bearing human glioma xenografts (i) retained their tumor tropism, (ii) continued to replicate CRAd-S-pk7 for more than a week after reaching the tumor site and (iii) successfully handed off CRAd-S-pk7 to glioma cells in vivo. Delivery via carrier cells reduced non-specific adenovirus distribution in the mouse brain. Moreover, we assessed biodistribution of loaded NSCs after intracranial injection in animal models semi-permissive to adenovirus replication, the Syrian hamster and cotton rat. NSCs did not migrate to distant organs and high levels of CRAd-S-pk7 DNA were observed only in the injected hemisphere. In conclusion, this optimized carrier system, with high efficiency of adenovirus delivery and minimal systemic toxicity, poses considerable advantages for anti-glioma Oncolytic Virotherapy.
Xavier Preville - One of the best experts on this subject based on the ideXlab platform.
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immune checkpoint blockade immunogenic chemotherapy or ifn α blockade boost the local and abscopal effects of Oncolytic Virotherapy
Cancer Research, 2017Co-Authors: Laetitia Fend, Takahiro Yamazaki, Christelle Remy, Catherine Fahrner, Murielle Gantzer, Virginie Nourtier, Xavier Preville, Eric QuemeneurAbstract:Athough the clinical efficacy of Oncolytic viruses has been demonstrated for local treatment, the ability to induce immune-mediated regression of distant metastases is still poorly documented. We report here that the engineered Oncolytic vaccinia virus VVWR-TK-RR--Fcu1 can induce immunogenic cell death and generate a systemic immune response. Effects on tumor growth and survival was largely driven by CD8+ T cells, and immune cell infiltrate in the tumor could be reprogrammed toward a higher ratio of effector T cells to regulatory CD4+ T cells. The key role of type 1 IFN pathway in Oncolytic Virotherapy was also highlighted, as we observed a strong abscopal response in Ifnar-/- tumors. In this model, single administration of virus directly into the tumors on one flank led to regression in the contralateral flank. Moreover, these effects were further enhanced when Oncolytic treatment was combined with immunogenic chemotherapy or with immune checkpoint blockade. Taken together, our results suggest how to safely improve the efficacy of local Oncolytic Virotherapy in patients whose tumors are characterized by dysregulated IFNα signaling. Cancer Res; 77(15); 4146-57. ©2017 AACR.
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abstract 4563 local and abscopal effects in Oncolytic Virotherapy are boosted by immune checkpoint blockade immunogenic chemotherapy or ifnar blockade
Cancer Research, 2017Co-Authors: Laetitia Fend, Guido Kroemer, Takahiro Yamazaki, Xavier Preville, Eric Quemeneur, Oliver Kepp, Julien Adam, Aurelien Marabelle, Jonathan M Pitt, Laurence ZitvogelAbstract:Athough the clinical efficacy of Oncolytic viruses has been demonstrated for local treatment, the ability to induce immune-mediated regression of distant metastases is still poorly documented. We here report that an engineered Oncolytic Vaccinia Virus, VVWR-TK-RR--Fcu1, is able to induce an immunogenic cell death and thus to generate a systemic immune response. Effect on tumor growth and survival is largely driven by CD8+ T-cells, and we could demonstrate that the immune cell infiltrate in the tumor could be reprogrammed towards a higher ratio of effector T-cells to regulatory CD4+ T-cells. The key role of the type 1-IFN pathway in Oncolytic Virotherapy was also highlighted, and we could show a strong abscopal response in Ifnar-/- tumors. In this model, the single administration of the virus directly into the tumors, on one flank, led to regression in the contralateral flank (i.e. opposite to the virus injection site). Moreover, we observed that these effects are further enhanced when the Oncolytic treatment is combined with either immunogenic chemotherapy such as oxaliplatin, or with immune checkpoint blockers such as anti-PD-1 or anti-CTLA-4. Altogether, these data suggest that local Oncolytic Virotherapy in patients with tumors altered in IFNAR signaling could increase immune-mediated abscopal regression of distant metastases. Citation Format: Laetitia Fend, Takahiro Yamazaki, Xavier Preville, Eric Quemeneur, Oliver Kepp, Julien Adam, Aurelien Marabelle, Jonathan Pitt, Guido Kroemer, Laurence Zitvogel. Local and abscopal effects in Oncolytic Virotherapy are boosted by immune checkpoint blockade, immunogenic chemotherapy, or IFNAR blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4563. doi:10.1158/1538-7445.AM2017-4563
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Oncolytic Virotherapy with an armed vaccinia virus in an orthotopic model of renal carcinoma is associated with modification of the tumor microenvironment
OncoImmunology, 2016Co-Authors: Laetitia Fend, Christelle Remyziller, Johann Foloppe, Juliette Kempf, Sandrine Cochin, Luc Barraud, Nathalie Accart, Philippe Erbs, Sylvie Fournel, Xavier PrevilleAbstract:Oncolytic Virotherapy is an emergent promising therapeutic approach for the treatment of cancer. We have constructed a vaccinia virus (WR strain) deleted for thymidine kinase (TK) and ribonucleotide reductase (RR) genes that expressed the fusion suicide gene FCU1 derived from the yeast cytosine deaminase and uracil phosphoribosyltransferase genes. We evaluated this construct (VV-FCU1) in the orthotopic model of renal carcinoma (RenCa). Systemic administration of VV-FCU1 resulted in orthotopic tumor growth inhibition, despite temporary expression of viral proteins. VV-FCU1 treatment was associated with an infiltration of tumors by CD8+ T lymphocytes and a decrease in the proportion of infiltrating Tregs, thus modifying the ratio of CD8+/CD4+ Treg in favor of CD8+cytotoxic T cells. We demonstrated that VV-FCU1 treatment prolonged survival of animals implanted with RenCa cells in kidney. Depletion of CD8+ T cells abolished the therapeutic effect of VV-FCU1 while depletion of CD4+ T cells enhanced its protective activity. Administration of the prodrug 5-fluorocytosine (5-FC) resulted in a sustained control of tumor growth but did not extend survival. This study shows the importance of CD4+ and CD8+ T cells in vaccinia virus-mediated Oncolytic Virotherapy and suggests that this approach may be evaluated for the treatment of human renal cell carcinoma.
