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Matthew M Seavey - One of the best experts on this subject based on the ideXlab platform.
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abstract 1460 generation of a novel Allogeneic Cell based gp96 ig ox40l cancer vaccine improves anti tumor immunity and long term memory t Cell generation
Cancer Research, 2019Co-Authors: Vikas Tahiliani, Louise Giffin, Jason Rose, Jayalakshmi Miriyala, Patrick Dillon, Jeff Hutchins, Matthew M SeaveyAbstract:Our technology is focused on developing a next generation Cellular vaccine platform – referred to as ComPACT (COMbination Pan-Antigen Cytotoxic Therapy), that incorporates a tumor antigen chaperone (gp96-Ig) with T-Cell costimulation (OX40L-Ig), into a single tumor Cell line that secretes both. Viagenpumatucel-L (HS-110; ImPACT), a human lung adenocarcinoma Cell line, stably transfected to express gp96-Ig is being tested in a phase 1/2 clinical trial (NCT#02439450) with checkpoint inhibition for NSCLC. A similar line is being generated that will complement HS-110, providing costimulation in the form of secreted OX40-Ig (HS-130). To model how the addition of human HS-130 to HS-110 may impact anti-tumor immune responses, we generated mouse surrogates of these human lines and established an analogous system, that treats tumor-bearing animals with tissue-matched irradiated cancer Cell lines (B16F10) expressing gp96-Ig (mHS-110) and OX40L-Ig (mHS-130) both expressing ovalbumin, as our model tumor-associated antigen. Single dose vaccination with mHS-110 identified that 1 to 10 million Cells (290 ng to 2,900 ng of secreted gp96-Ig) provided sufficient anti-tumor CD8+ T-Cell expansion, in vivo (*p Citation Format: Vikas Tahiliani, Jayalakshmi Miriyala, Patrick Dillon, Jason Rose, Louise Giffin, Jeff Hutchins, Matthew M. Seavey. Generation of a novel, Allogeneic Cell-based, Gp96-Ig/OX40L cancer vaccine, improves anti-tumor immunity and long-term memory T-Cell generation [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 1460.
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effect on anti tumor immunity and long term memory cd8 t Cell generation with a novel Allogeneic Cell based gp96 ig ox40l cancer vaccine
Journal of Clinical Oncology, 2019Co-Authors: Jeff Hutchins, Jason Rose, Vikas Tahiliani, Jayalakshmi Miriyala, Patrick Dillon, Matthew M SeaveyAbstract:e14016Background: We are focused on developing and optimizing a next generation Cellular vaccine platform – referred to as ComPACT (COMbination Pan-Antigen Cytotoxic Therapy), that incorporates a t...
Bernard P Mahon - One of the best experts on this subject based on the ideXlab platform.
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Cell contact prostaglandin e2 and transforming growth factor beta 1 play non redundant roles in human mesenchymal stem Cell induction of cd4 cd25highforkhead box p3 regulatory t Cells
Clinical and Experimental Immunology, 2008Co-Authors: Karen English, Jennifer M Ryan, Laura M Tobin, Mary Murphy, Frank Barry, Bernard P MahonAbstract:Adult human mesenchymal stromal or stem Cells (MSC) can differentiate into a variety of Cell types and are candidate Cellular therapeutics in regenerative medicine. Surprisingly, these Cells also display multiple potent immunomodulatory capabilities, including allosuppression, making Allogeneic Cell therapy a possibility. The exact mechanisms involved in regulatory T Cell induction by Allogeneic human MSC was examined, using purified CD4+ populations and well-characterized bone marrow-derived adult human MSC. Allogeneic MSC were shown to induce forkhead box P3 (FoxP3)+ and CD25+ mRNA and protein expression in CD4+ T Cells. This phenomenon required direct contact between MSC and purified T Cells, although Cell contact was not required for MSC induction of FoxP3 expression in an unseparated mononuclear Cell population. In addition, through use of antagonists and neutralizing antibodies, MSC-derived prostaglandins and transforming growth factor (TGF)-beta1 were shown to have a non-redundant role in the induction of CD4+CD25+FoxP3+ T Cells. Purified CD4+CD25+ T Cells induced by MSC co-culture expressed TGF-beta1 and were able to suppress alloantigen-driven proliferative responses in mixed lymphocyte reaction. These data clarify the mechanisms of human MSC-mediated allosuppression, supporting a sequential process of regulatory T Cell induction involving direct MSC contact with CD4+ Cells followed by both prostaglandin E(2) and TGF-beta1 expression. Overall, this study provides a rational basis for ongoing clinical studies involving Allogeneic MSC.
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Cell contact prostaglandin e2 and transforming growth factor beta 1 play non redundant roles in human mesenchymal stem Cell induction of cd4 cd25highforkhead box p3 regulatory t Cells
Clinical and Experimental Immunology, 2008Co-Authors: Karen English, Jennifer M Ryan, Laura M Tobin, Mary Murphy, Frank Barry, Bernard P MahonAbstract:Adult human mesenchymal stromal or stem Cells (MSC) can differentiate into a variety of Cell types and are candidate Cellular therapeutics in regenerative medicine. Surprisingly, these Cells also display multiple potent immunomodulatory capabilities, including allosuppression, making Allogeneic Cell therapy a possibility. The exact mechanisms involved in regulatory T Cell induction by Allogeneic human MSC was examined, using purified CD4+ populations and well-characterized bone marrow-derived adult human MSC. Allogeneic MSC were shown to induce forkhead box P3 (FoxP3)+ and CD25+ mRNA and protein expression in CD4+ T Cells. This phenomenon required direct contact between MSC and purified T Cells, although Cell contact was not required for MSC induction of FoxP3 expression in an unseparated mononuclear Cell population. In addition, through use of antagonists and neutralizing antibodies, MSC-derived prostaglandins and transforming growth factor (TGF)-β1 were shown to have a non-redundant role in the induction of CD4+CD25+FoxP3+ T Cells. Purified CD4+CD25+ T Cells induced by MSC co-culture expressed TGF-β1 and were able to suppress alloantigen-driven proliferative responses in mixed lymphocyte reaction. These data clarify the mechanisms of human MSC-mediated allosuppression, supporting a sequential process of regulatory T Cell induction involving direct MSC contact with CD4+ Cells followed by both prostaglandin E2 and TGF-β1 expression. Overall, this study provides a rational basis for ongoing clinical studies involving Allogeneic MSC.
Jason Rose - One of the best experts on this subject based on the ideXlab platform.
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abstract 1460 generation of a novel Allogeneic Cell based gp96 ig ox40l cancer vaccine improves anti tumor immunity and long term memory t Cell generation
Cancer Research, 2019Co-Authors: Vikas Tahiliani, Louise Giffin, Jason Rose, Jayalakshmi Miriyala, Patrick Dillon, Jeff Hutchins, Matthew M SeaveyAbstract:Our technology is focused on developing a next generation Cellular vaccine platform – referred to as ComPACT (COMbination Pan-Antigen Cytotoxic Therapy), that incorporates a tumor antigen chaperone (gp96-Ig) with T-Cell costimulation (OX40L-Ig), into a single tumor Cell line that secretes both. Viagenpumatucel-L (HS-110; ImPACT), a human lung adenocarcinoma Cell line, stably transfected to express gp96-Ig is being tested in a phase 1/2 clinical trial (NCT#02439450) with checkpoint inhibition for NSCLC. A similar line is being generated that will complement HS-110, providing costimulation in the form of secreted OX40-Ig (HS-130). To model how the addition of human HS-130 to HS-110 may impact anti-tumor immune responses, we generated mouse surrogates of these human lines and established an analogous system, that treats tumor-bearing animals with tissue-matched irradiated cancer Cell lines (B16F10) expressing gp96-Ig (mHS-110) and OX40L-Ig (mHS-130) both expressing ovalbumin, as our model tumor-associated antigen. Single dose vaccination with mHS-110 identified that 1 to 10 million Cells (290 ng to 2,900 ng of secreted gp96-Ig) provided sufficient anti-tumor CD8+ T-Cell expansion, in vivo (*p Citation Format: Vikas Tahiliani, Jayalakshmi Miriyala, Patrick Dillon, Jason Rose, Louise Giffin, Jeff Hutchins, Matthew M. Seavey. Generation of a novel, Allogeneic Cell-based, Gp96-Ig/OX40L cancer vaccine, improves anti-tumor immunity and long-term memory T-Cell generation [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 1460.
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effect on anti tumor immunity and long term memory cd8 t Cell generation with a novel Allogeneic Cell based gp96 ig ox40l cancer vaccine
Journal of Clinical Oncology, 2019Co-Authors: Jeff Hutchins, Jason Rose, Vikas Tahiliani, Jayalakshmi Miriyala, Patrick Dillon, Matthew M SeaveyAbstract:e14016Background: We are focused on developing and optimizing a next generation Cellular vaccine platform – referred to as ComPACT (COMbination Pan-Antigen Cytotoxic Therapy), that incorporates a t...
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gp96 ig costimulator ox40l icosl or 4 1bbl combination vaccine improves t Cell priming and enhances immunity memory and tumor elimination
Cancer immunology research, 2016Co-Authors: George Fromm, Suresh De Silva, Louise Giffin, Jason Rose, Taylor H SchreiberAbstract:T-Cell costimulation typically occurs in a defined microenvironment that is not recapitulated by agonistic antibody therapy. To deliver such stimulation under more favorable conditions, we investigated whether an Allogeneic Cell-based vaccine that secreted Fc-OX40L, Fc-ICOSL, or Fc-4-1BBL would activate and expand T Cells comparably with systemically administered agonist antibodies. Among these costimulators, locally secreted Fc-OX40L provided superior priming of antigen-specific CD8(+) T Cells, compared with combinations with OX40 antibodies or vaccine alone. Vaccine-expressed Fc-OX40L also stimulated IFNγ, TNFα, granzyme B, and IL2 by antigen-specific CD8(+) T Cells similarly to OX40 antibodies, without off-target consequences such as proinflammatory cytokine induction. Vaccine-secreted Fc-OX40L increased CD127(+)KLRG-1(-) memory precursor Cells during the contraction phase, resulting in improved proliferation upon secondary antigen challenge, as compared with OX40 antibody. A Cell-based vaccine cosecreting gp96-Ig and Fc-OX40L led to even more pronounced tumor control, complete tumor rejection, and increased tumor antigen-specific T-Cell proliferation, including in tumor-infiltrating lymphocytes, as compared with combinations of gp96-Ig vaccine and OX40 antibodies, in mice with established melanoma or colorectal carcinoma. These data suggest that local modulation of the vaccine microenvironment has unexpected advantages over systemic costimulation with agonistic antibodies, which may simplify the clinical translation of such combination immunotherapies into humans. Cancer Immunol Res; 4(9); 766-78. ©2016 AACR.
Christopher J Hewitt - One of the best experts on this subject based on the ideXlab platform.
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characterization of human mesenchymal stem Cells from multiple donors and the implications for large scale bioprocess development
Biochemical Engineering Journal, 2016Co-Authors: Thomas R J Heathman, Qasim A Rafiq, Christopher J Hewitt, Karen Coopman, Alexander K C Chan, A W Nienow, Bo KaraAbstract:Cell-based therapies have the potential to contribute to global healthcare, whereby the use of living Cells and tissues can be used as medicinal therapies. Despite this potential, many challenges remain before the full value of this emerging field can be realized. The characterization of input material for Cell-based therapy bioprocesses from multiple donors is necessary to identify and understand the potential implications of input variation on process development. In this work, we have characterized bone marrow derived human mesenchymal stem Cells (BM-hMSCs) from multiple donors and discussed the implications of the measurable input variation on the development of autologous and Allogeneic Cell-based therapy manufacturing processes. The range of cumulative population doublings across the five BM-hMSC lines over 30 days of culture was 5.93, with an 18.2% range in colony forming efficiency at the end of the culture process and a 55.1% difference in the production of interleukin-6 between these Cell lines. It has been demonstrated that this variation results in a range in the process time between these donor hMSC lines for a hypothetical product of over 13 days, creating potential batch timing issues when manufacturing products from multiple patients. All BM-hMSC donor lines demonstrated conformity to the ISCT criteria but showed a difference in Cell morphology. Metabolite analysis showed that hMSCs from the different donors have a range in glucose consumption of 26.98 pmol Cell−1 day−1, Lactate production of 29.45 pmol Cell−1 day−1 and ammonium production of 1.35 pmol Cell−1 day−1, demonstrating the extent of donor variability throughout the expansion process. Measuring informative product attributes during process development will facilitate progress towards consistent manufacturing processes, a critical step in the translation Cell-based therapies.
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systematic microcarrier screening and agitated culture conditions improves human mesenchymal stem Cell yield in bioreactors
Biotechnology Journal, 2016Co-Authors: Qasim A Rafiq, Karen Coopman, Alvin W Nienow, Christopher J HewittAbstract:Production of human mesenchymal stem Cells for Allogeneic Cell therapies requires scalable, cost-effective manufacturing processes. Microcarriers enable the culture of anchorage-dependent Cells in stirred-tank bioreactors. However, no robust, transferable methodology for microcarrier selection exists, with studies providing little or no reason explaining why a microcarrier was employed. We systematically evaluated 13 microcarriers for human bone marrow-derived MSC (hBM-MSCs) expansion from three donors to establish a reproducible and transferable methodology for microcarrier selection. Monolayer studies demonstrated input Cell line variability with respect to growth kinetics and metabolite flux. HBM-MSC1 underwent more cumulative population doublings over three passages in comparison to hBM-MSC2 and hBM-MSC3. In 100 mL spinner flasks, agitated conditions were significantly better than static conditions, irrespective of donor, and relative microcarrier performance was identical where the same microcarriers outperformed others with respect to growth kinetics and metabolite flux. Relative growth kinetics between donor Cells on the microcarriers were the same as the monolayer study. Plastic microcarriers were selected as the optimal microcarrier for hBM-MSC expansion. HBM-MSCs were successfully harvested and characterised, demonstrating hBM-MSC immunophenotype and differentiation capacity. This approach provides a systematic method for microcarrier selection, and the findings identify potentially significant bioprocessing implications for microcarrier-based Allogeneic Cell therapy manufacture. Large-scale production of human bone-marrow derived mesenchymal stem Cells (hBM-MSCs) requires expansion on microcarriers in agitated systems. This study demonstrates the importance of microcarrier selection and presents a systematic methodology for selection of an optimal microcarrier. The study also highlights the impact of an agitated culture environment in comparison to a static system, resulting in a significantly higher hBM-MSC yield under agitated conditions.
Vikas Tahiliani - One of the best experts on this subject based on the ideXlab platform.
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abstract 1460 generation of a novel Allogeneic Cell based gp96 ig ox40l cancer vaccine improves anti tumor immunity and long term memory t Cell generation
Cancer Research, 2019Co-Authors: Vikas Tahiliani, Louise Giffin, Jason Rose, Jayalakshmi Miriyala, Patrick Dillon, Jeff Hutchins, Matthew M SeaveyAbstract:Our technology is focused on developing a next generation Cellular vaccine platform – referred to as ComPACT (COMbination Pan-Antigen Cytotoxic Therapy), that incorporates a tumor antigen chaperone (gp96-Ig) with T-Cell costimulation (OX40L-Ig), into a single tumor Cell line that secretes both. Viagenpumatucel-L (HS-110; ImPACT), a human lung adenocarcinoma Cell line, stably transfected to express gp96-Ig is being tested in a phase 1/2 clinical trial (NCT#02439450) with checkpoint inhibition for NSCLC. A similar line is being generated that will complement HS-110, providing costimulation in the form of secreted OX40-Ig (HS-130). To model how the addition of human HS-130 to HS-110 may impact anti-tumor immune responses, we generated mouse surrogates of these human lines and established an analogous system, that treats tumor-bearing animals with tissue-matched irradiated cancer Cell lines (B16F10) expressing gp96-Ig (mHS-110) and OX40L-Ig (mHS-130) both expressing ovalbumin, as our model tumor-associated antigen. Single dose vaccination with mHS-110 identified that 1 to 10 million Cells (290 ng to 2,900 ng of secreted gp96-Ig) provided sufficient anti-tumor CD8+ T-Cell expansion, in vivo (*p Citation Format: Vikas Tahiliani, Jayalakshmi Miriyala, Patrick Dillon, Jason Rose, Louise Giffin, Jeff Hutchins, Matthew M. Seavey. Generation of a novel, Allogeneic Cell-based, Gp96-Ig/OX40L cancer vaccine, improves anti-tumor immunity and long-term memory T-Cell generation [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 1460.
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effect on anti tumor immunity and long term memory cd8 t Cell generation with a novel Allogeneic Cell based gp96 ig ox40l cancer vaccine
Journal of Clinical Oncology, 2019Co-Authors: Jeff Hutchins, Jason Rose, Vikas Tahiliani, Jayalakshmi Miriyala, Patrick Dillon, Matthew M SeaveyAbstract:e14016Background: We are focused on developing and optimizing a next generation Cellular vaccine platform – referred to as ComPACT (COMbination Pan-Antigen Cytotoxic Therapy), that incorporates a t...