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Vuong Trieu - One of the best experts on this subject based on the ideXlab platform.
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Abstract 3968: OT-101/Chemotherapy - A novel mechanism of action (MOA) in pancreatic Cancer Immunization therapy
Clinical Research (Excluding Clinical Trials), 2019Co-Authors: David Nam, Larn Hwang, Vuong TrieuAbstract:Background: OT-101 is a phosphorothioate antisense oligodeoxynucleotide targeting the human TGF-β2 mRNA. OT-101 breaks down immune tolerance and activates immunity against the tumor. The Subsequent Chemotherapy (SC) releases tumor antigens and boosts the immunity response along with further epitope expansion. The phase 1/2 clinical data for OT-101/SC is presented here along with supporting preclinical MOA studies. Methods: Total of 37 pts, 2nd line and beyond received OT-101 with option to go on SC (OT-101/SC) or Best Supportive Care (BSC) (OT-101/BSC). Overall survival (OS) was compared using log-rank statistics. Stratification by treatment line, schedule, metastasis location, disease control (DC), and baseline CA19-9, was performed. For cytokine analysis, plasma levels of 31 cyto-/chemokine were measured over 8 time points during 3 cycles of intravenous OT-101 therapy and a subset of 12 patients. Results: In vitro cell kill assay and in vivo xenograft study were performed with human PBMC and OT-101. OT-101 reduced TGF-β2 secretion and increased LAK cell-activity against all tumor lines by 400% and 364% in comparison to the untreated control and the Lipofectin control, respectively. Addition of active rh-TGF-β2 protein suppressed the cytotoxic activity of the immune cells in a dose dependent manner. Preclinical- LS174T xenograft was treated with PBMC or PBMC + OT-101. OT-101 significantly enhanced the activity of PBMC against the xenograft. Median OS (mOS) of the 18 pts receiving OT-101/SC was 9.4mos vs. the 19 pts on OT-101/BSC (2.8mos, p=0.0004). Pts with only liver mets had a mOS of 9.5mos while those with liver mets and others only had a mOS of 4.7mos (p=0.0077). Among the former, one patient had complete response beyond 77.3mos and another had stable disease with OS of 40.3mos. OS was higher for liver mets. only group with OT-101/SC - 12.4mos versus 1.9mos, p=0.0006. There were 16 of 37 pts with DC, with mOS of 9.7mos vs. 3.0mos (p Conclusions: Escalating Intratumoral heterogeneity (IH) resulting in xenogenization, which is countered by overexpression of TGF-β. Here we report on the use of OT-101/SC to break immune tolerance to pancreatic Cancer (PC) for the cure. The MOA for OT-101/SC is consistent with the reactivation of immunity during TGF-β suppression and subsequent boosting/expansion of immunity during SC. Contrary to traditional tumor vaccine- this is universally applicable to all patients. Citation Format: David Nam, Larn Hwang, Vuong Trieu. OT-101/Chemotherapy - A novel mechanism of action (MOA) in pancreatic Cancer Immunization therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3968.
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abstract 3968 ot 101 chemotherapy a novel mechanism of action moa in pancreatic Cancer Immunization therapy
Cancer Research, 2019Co-Authors: David Nam, Larn Hwang, Vuong TrieuAbstract:Background: OT-101 is a phosphorothioate antisense oligodeoxynucleotide targeting the human TGF-β2 mRNA. OT-101 breaks down immune tolerance and activates immunity against the tumor. The Subsequent Chemotherapy (SC) releases tumor antigens and boosts the immunity response along with further epitope expansion. The phase 1/2 clinical data for OT-101/SC is presented here along with supporting preclinical MOA studies. Methods: Total of 37 pts, 2nd line and beyond received OT-101 with option to go on SC (OT-101/SC) or Best Supportive Care (BSC) (OT-101/BSC). Overall survival (OS) was compared using log-rank statistics. Stratification by treatment line, schedule, metastasis location, disease control (DC), and baseline CA19-9, was performed. For cytokine analysis, plasma levels of 31 cyto-/chemokine were measured over 8 time points during 3 cycles of intravenous OT-101 therapy and a subset of 12 patients. Results: In vitro cell kill assay and in vivo xenograft study were performed with human PBMC and OT-101. OT-101 reduced TGF-β2 secretion and increased LAK cell-activity against all tumor lines by 400% and 364% in comparison to the untreated control and the Lipofectin control, respectively. Addition of active rh-TGF-β2 protein suppressed the cytotoxic activity of the immune cells in a dose dependent manner. Preclinical- LS174T xenograft was treated with PBMC or PBMC + OT-101. OT-101 significantly enhanced the activity of PBMC against the xenograft. Median OS (mOS) of the 18 pts receiving OT-101/SC was 9.4mos vs. the 19 pts on OT-101/BSC (2.8mos, p=0.0004). Pts with only liver mets had a mOS of 9.5mos while those with liver mets and others only had a mOS of 4.7mos (p=0.0077). Among the former, one patient had complete response beyond 77.3mos and another had stable disease with OS of 40.3mos. OS was higher for liver mets. only group with OT-101/SC - 12.4mos versus 1.9mos, p=0.0006. There were 16 of 37 pts with DC, with mOS of 9.7mos vs. 3.0mos (p Conclusions: Escalating Intratumoral heterogeneity (IH) resulting in xenogenization, which is countered by overexpression of TGF-β. Here we report on the use of OT-101/SC to break immune tolerance to pancreatic Cancer (PC) for the cure. The MOA for OT-101/SC is consistent with the reactivation of immunity during TGF-β suppression and subsequent boosting/expansion of immunity during SC. Contrary to traditional tumor vaccine- this is universally applicable to all patients. Citation Format: David Nam, Larn Hwang, Vuong Trieu. OT-101/Chemotherapy - A novel mechanism of action (MOA) in pancreatic Cancer Immunization therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3968.
David Nam - One of the best experts on this subject based on the ideXlab platform.
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Abstract 3968: OT-101/Chemotherapy - A novel mechanism of action (MOA) in pancreatic Cancer Immunization therapy
Clinical Research (Excluding Clinical Trials), 2019Co-Authors: David Nam, Larn Hwang, Vuong TrieuAbstract:Background: OT-101 is a phosphorothioate antisense oligodeoxynucleotide targeting the human TGF-β2 mRNA. OT-101 breaks down immune tolerance and activates immunity against the tumor. The Subsequent Chemotherapy (SC) releases tumor antigens and boosts the immunity response along with further epitope expansion. The phase 1/2 clinical data for OT-101/SC is presented here along with supporting preclinical MOA studies. Methods: Total of 37 pts, 2nd line and beyond received OT-101 with option to go on SC (OT-101/SC) or Best Supportive Care (BSC) (OT-101/BSC). Overall survival (OS) was compared using log-rank statistics. Stratification by treatment line, schedule, metastasis location, disease control (DC), and baseline CA19-9, was performed. For cytokine analysis, plasma levels of 31 cyto-/chemokine were measured over 8 time points during 3 cycles of intravenous OT-101 therapy and a subset of 12 patients. Results: In vitro cell kill assay and in vivo xenograft study were performed with human PBMC and OT-101. OT-101 reduced TGF-β2 secretion and increased LAK cell-activity against all tumor lines by 400% and 364% in comparison to the untreated control and the Lipofectin control, respectively. Addition of active rh-TGF-β2 protein suppressed the cytotoxic activity of the immune cells in a dose dependent manner. Preclinical- LS174T xenograft was treated with PBMC or PBMC + OT-101. OT-101 significantly enhanced the activity of PBMC against the xenograft. Median OS (mOS) of the 18 pts receiving OT-101/SC was 9.4mos vs. the 19 pts on OT-101/BSC (2.8mos, p=0.0004). Pts with only liver mets had a mOS of 9.5mos while those with liver mets and others only had a mOS of 4.7mos (p=0.0077). Among the former, one patient had complete response beyond 77.3mos and another had stable disease with OS of 40.3mos. OS was higher for liver mets. only group with OT-101/SC - 12.4mos versus 1.9mos, p=0.0006. There were 16 of 37 pts with DC, with mOS of 9.7mos vs. 3.0mos (p Conclusions: Escalating Intratumoral heterogeneity (IH) resulting in xenogenization, which is countered by overexpression of TGF-β. Here we report on the use of OT-101/SC to break immune tolerance to pancreatic Cancer (PC) for the cure. The MOA for OT-101/SC is consistent with the reactivation of immunity during TGF-β suppression and subsequent boosting/expansion of immunity during SC. Contrary to traditional tumor vaccine- this is universally applicable to all patients. Citation Format: David Nam, Larn Hwang, Vuong Trieu. OT-101/Chemotherapy - A novel mechanism of action (MOA) in pancreatic Cancer Immunization therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3968.
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abstract 3968 ot 101 chemotherapy a novel mechanism of action moa in pancreatic Cancer Immunization therapy
Cancer Research, 2019Co-Authors: David Nam, Larn Hwang, Vuong TrieuAbstract:Background: OT-101 is a phosphorothioate antisense oligodeoxynucleotide targeting the human TGF-β2 mRNA. OT-101 breaks down immune tolerance and activates immunity against the tumor. The Subsequent Chemotherapy (SC) releases tumor antigens and boosts the immunity response along with further epitope expansion. The phase 1/2 clinical data for OT-101/SC is presented here along with supporting preclinical MOA studies. Methods: Total of 37 pts, 2nd line and beyond received OT-101 with option to go on SC (OT-101/SC) or Best Supportive Care (BSC) (OT-101/BSC). Overall survival (OS) was compared using log-rank statistics. Stratification by treatment line, schedule, metastasis location, disease control (DC), and baseline CA19-9, was performed. For cytokine analysis, plasma levels of 31 cyto-/chemokine were measured over 8 time points during 3 cycles of intravenous OT-101 therapy and a subset of 12 patients. Results: In vitro cell kill assay and in vivo xenograft study were performed with human PBMC and OT-101. OT-101 reduced TGF-β2 secretion and increased LAK cell-activity against all tumor lines by 400% and 364% in comparison to the untreated control and the Lipofectin control, respectively. Addition of active rh-TGF-β2 protein suppressed the cytotoxic activity of the immune cells in a dose dependent manner. Preclinical- LS174T xenograft was treated with PBMC or PBMC + OT-101. OT-101 significantly enhanced the activity of PBMC against the xenograft. Median OS (mOS) of the 18 pts receiving OT-101/SC was 9.4mos vs. the 19 pts on OT-101/BSC (2.8mos, p=0.0004). Pts with only liver mets had a mOS of 9.5mos while those with liver mets and others only had a mOS of 4.7mos (p=0.0077). Among the former, one patient had complete response beyond 77.3mos and another had stable disease with OS of 40.3mos. OS was higher for liver mets. only group with OT-101/SC - 12.4mos versus 1.9mos, p=0.0006. There were 16 of 37 pts with DC, with mOS of 9.7mos vs. 3.0mos (p Conclusions: Escalating Intratumoral heterogeneity (IH) resulting in xenogenization, which is countered by overexpression of TGF-β. Here we report on the use of OT-101/SC to break immune tolerance to pancreatic Cancer (PC) for the cure. The MOA for OT-101/SC is consistent with the reactivation of immunity during TGF-β suppression and subsequent boosting/expansion of immunity during SC. Contrary to traditional tumor vaccine- this is universally applicable to all patients. Citation Format: David Nam, Larn Hwang, Vuong Trieu. OT-101/Chemotherapy - A novel mechanism of action (MOA) in pancreatic Cancer Immunization therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3968.
Larn Hwang - One of the best experts on this subject based on the ideXlab platform.
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Abstract 3968: OT-101/Chemotherapy - A novel mechanism of action (MOA) in pancreatic Cancer Immunization therapy
Clinical Research (Excluding Clinical Trials), 2019Co-Authors: David Nam, Larn Hwang, Vuong TrieuAbstract:Background: OT-101 is a phosphorothioate antisense oligodeoxynucleotide targeting the human TGF-β2 mRNA. OT-101 breaks down immune tolerance and activates immunity against the tumor. The Subsequent Chemotherapy (SC) releases tumor antigens and boosts the immunity response along with further epitope expansion. The phase 1/2 clinical data for OT-101/SC is presented here along with supporting preclinical MOA studies. Methods: Total of 37 pts, 2nd line and beyond received OT-101 with option to go on SC (OT-101/SC) or Best Supportive Care (BSC) (OT-101/BSC). Overall survival (OS) was compared using log-rank statistics. Stratification by treatment line, schedule, metastasis location, disease control (DC), and baseline CA19-9, was performed. For cytokine analysis, plasma levels of 31 cyto-/chemokine were measured over 8 time points during 3 cycles of intravenous OT-101 therapy and a subset of 12 patients. Results: In vitro cell kill assay and in vivo xenograft study were performed with human PBMC and OT-101. OT-101 reduced TGF-β2 secretion and increased LAK cell-activity against all tumor lines by 400% and 364% in comparison to the untreated control and the Lipofectin control, respectively. Addition of active rh-TGF-β2 protein suppressed the cytotoxic activity of the immune cells in a dose dependent manner. Preclinical- LS174T xenograft was treated with PBMC or PBMC + OT-101. OT-101 significantly enhanced the activity of PBMC against the xenograft. Median OS (mOS) of the 18 pts receiving OT-101/SC was 9.4mos vs. the 19 pts on OT-101/BSC (2.8mos, p=0.0004). Pts with only liver mets had a mOS of 9.5mos while those with liver mets and others only had a mOS of 4.7mos (p=0.0077). Among the former, one patient had complete response beyond 77.3mos and another had stable disease with OS of 40.3mos. OS was higher for liver mets. only group with OT-101/SC - 12.4mos versus 1.9mos, p=0.0006. There were 16 of 37 pts with DC, with mOS of 9.7mos vs. 3.0mos (p Conclusions: Escalating Intratumoral heterogeneity (IH) resulting in xenogenization, which is countered by overexpression of TGF-β. Here we report on the use of OT-101/SC to break immune tolerance to pancreatic Cancer (PC) for the cure. The MOA for OT-101/SC is consistent with the reactivation of immunity during TGF-β suppression and subsequent boosting/expansion of immunity during SC. Contrary to traditional tumor vaccine- this is universally applicable to all patients. Citation Format: David Nam, Larn Hwang, Vuong Trieu. OT-101/Chemotherapy - A novel mechanism of action (MOA) in pancreatic Cancer Immunization therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3968.
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abstract 3968 ot 101 chemotherapy a novel mechanism of action moa in pancreatic Cancer Immunization therapy
Cancer Research, 2019Co-Authors: David Nam, Larn Hwang, Vuong TrieuAbstract:Background: OT-101 is a phosphorothioate antisense oligodeoxynucleotide targeting the human TGF-β2 mRNA. OT-101 breaks down immune tolerance and activates immunity against the tumor. The Subsequent Chemotherapy (SC) releases tumor antigens and boosts the immunity response along with further epitope expansion. The phase 1/2 clinical data for OT-101/SC is presented here along with supporting preclinical MOA studies. Methods: Total of 37 pts, 2nd line and beyond received OT-101 with option to go on SC (OT-101/SC) or Best Supportive Care (BSC) (OT-101/BSC). Overall survival (OS) was compared using log-rank statistics. Stratification by treatment line, schedule, metastasis location, disease control (DC), and baseline CA19-9, was performed. For cytokine analysis, plasma levels of 31 cyto-/chemokine were measured over 8 time points during 3 cycles of intravenous OT-101 therapy and a subset of 12 patients. Results: In vitro cell kill assay and in vivo xenograft study were performed with human PBMC and OT-101. OT-101 reduced TGF-β2 secretion and increased LAK cell-activity against all tumor lines by 400% and 364% in comparison to the untreated control and the Lipofectin control, respectively. Addition of active rh-TGF-β2 protein suppressed the cytotoxic activity of the immune cells in a dose dependent manner. Preclinical- LS174T xenograft was treated with PBMC or PBMC + OT-101. OT-101 significantly enhanced the activity of PBMC against the xenograft. Median OS (mOS) of the 18 pts receiving OT-101/SC was 9.4mos vs. the 19 pts on OT-101/BSC (2.8mos, p=0.0004). Pts with only liver mets had a mOS of 9.5mos while those with liver mets and others only had a mOS of 4.7mos (p=0.0077). Among the former, one patient had complete response beyond 77.3mos and another had stable disease with OS of 40.3mos. OS was higher for liver mets. only group with OT-101/SC - 12.4mos versus 1.9mos, p=0.0006. There were 16 of 37 pts with DC, with mOS of 9.7mos vs. 3.0mos (p Conclusions: Escalating Intratumoral heterogeneity (IH) resulting in xenogenization, which is countered by overexpression of TGF-β. Here we report on the use of OT-101/SC to break immune tolerance to pancreatic Cancer (PC) for the cure. The MOA for OT-101/SC is consistent with the reactivation of immunity during TGF-β suppression and subsequent boosting/expansion of immunity during SC. Contrary to traditional tumor vaccine- this is universally applicable to all patients. Citation Format: David Nam, Larn Hwang, Vuong Trieu. OT-101/Chemotherapy - A novel mechanism of action (MOA) in pancreatic Cancer Immunization therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3968.
N Mach - One of the best experts on this subject based on the ideXlab platform.
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Cell encapsulation technology as a novel strategy for human anti-tumor immunotherapy
Cancer Gene Therapy, 2011Co-Authors: Frank Schwenter, S Zarei, V Padrun, R C Mulligan, Nicolas Bouché, P. Morel, N MachAbstract:Granulocyte-macrophage colony-stimulating factor (GM-CSF) as an adjuvant in autologous cell-based anti-tumor immunotherapy has recently been approved for clinical application. To avoid the need for individualized processing of autologous cells, we developed a novel strategy based on the encapsulation of GM-CSF-secreting human allogeneic cells. GM-CSF-producing K562 cells showed high, stable and reproducible cytokine secretion when enclosed into macrocapsules. For clinical development, the cryopreservation of these devices is critical. Thawing of capsules frozen at different time points displayed differences in GM-CSF release shortly after thawing. However, similar secretion values to those of non-frozen control capsules were obtained 8 days after thawing at a rate of >1000 ng GM-CSF per capsule every 24 h. For future human application, longer and reinforced capsules were designed. After irradiation and cryopreservation, these capsules produced >300 ng GM-CSF per capsule every 24 h 1 week after thawing. The in vivo implantation of encapsulated K562 cells was evaluated in mice and showed preserved cell survival. Finally, as a proof of principle of biological activity, capsules containing B16-GM-CSF allogeneic cells implanted in mice induced a prompt inflammatory reaction. The ability to reliably achieve high adjuvant release using a standardized procedure may lead to a new clinical application of GM-CSF in cell-based Cancer Immunization.
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cell encapsulation technology as a novel strategy for human anti tumor immunotherapy
Cancer Gene Therapy, 2011Co-Authors: Frank Schwenter, S Zarei, V Padrun, R C Mulligan, Nicolas Bouché, P. Morel, N MachAbstract:Granulocyte-macrophage colony-stimulating factor (GM-CSF) as an adjuvant in autologous cell-based anti-tumor immunotherapy has recently been approved for clinical application. To avoid the need for individualized processing of autologous cells, we developed a novel strategy based on the encapsulation of GM-CSF-secreting human allogeneic cells. GM-CSF-producing K562 cells showed high, stable and reproducible cytokine secretion when enclosed into macrocapsules. For clinical development, the cryopreservation of these devices is critical. Thawing of capsules frozen at different time points displayed differences in GM-CSF release shortly after thawing. However, similar secretion values to those of non-frozen control capsules were obtained 8 days after thawing at a rate of >1000 ng GM-CSF per capsule every 24 h. For future human application, longer and reinforced capsules were designed. After irradiation and cryopreservation, these capsules produced >300 ng GM-CSF per capsule every 24 h 1 week after thawing. The in vivo implantation of encapsulated K562 cells was evaluated in mice and showed preserved cell survival. Finally, as a proof of principle of biological activity, capsules containing B16-GM-CSF allogeneic cells implanted in mice induced a prompt inflammatory reaction. The ability to reliably achieve high adjuvant release using a standardized procedure may lead to a new clinical application of GM-CSF in cell-based Cancer Immunization. Cancer Gene Therapy (2011) 18, 553-562; doi:10.1038/cgt.2011.22; published online 13 May 2011
Robert C. Rees - One of the best experts on this subject based on the ideXlab platform.
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Genetically modified tumour cells for Cancer Immunization
Cancer Immunology, 2001Co-Authors: Stephen Todryk, Selman A. Ali, Angus G. Dalgleish, Robert C. ReesAbstract:Whole tumour cells are a logical basis for generating immunity against the Cancers they comprise or represent. In order to alert the immune system to respond to the tumour antigens intervention is required. This can be achieved by transfection of the tumour cells with genes encoding a variety of immunostimulatory molecules. The most obvious approach is the transduction of tumour cells taken from the body with genes that encode molecules (such as cytokines and costimulatory molecules) that enhance T cell or antigen presenting cell function. Irradiated cells are then re-injected as a Cancer vaccine and an anti-tumour immune response is generated that can destroy tumour cells. Molecules that effect antigen presenting cell function, such as Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF), appear to hold the most promise as demonstrated in preclinical and early clinical studies. The direct delivery of immunostimulatory molecule genes to tumours in vivo also shows some efficacy, especially the suicide gene Herpes Simplex Virus thymidine kinase. Future clinical trials in earlier stage patients will provide the clearest indication of the efficacy of Immunization with transduced tumour cells since tumour burdens will be lower and immunocompetence will be better than in present phase I/II trials.
