Enhanced clinical-scale manufacturing of TCR transduced T-cells using closed culture system modules

Background Genetic engineering of T-cells to express specific T cell receptors (TCR) has emerged as a novel strategy to treat various malignancies. More widespread utilization of these types of therapies has been somewhat constrained by the lack of closed culture processes capable of expanding suffi...
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Autor*in:	Jin, Jianjian [verfasserIn] Gkitsas, Nikolaos Fellowes, Vicki S. Ren, Jiaqiang Feldman, Steven A. Hinrichs, Christian S. Stroncek, David F. Highfill, Steven L.

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2018

Schlagwörter:	E6 HPV E7 HPV HPV-16+ T-cell receptor Cellular therapy Cancer immunotherapy Cervical cancer Epithelial cancer T-cell manufacturing

Anmerkung:	© The Author(s) 2018

Übergeordnetes Werk:	Enthalten in: Journal of translational medicine - London : BioMed Central, 2003, 16(2018), 1 vom: 24. Jan.
Übergeordnetes Werk:	volume:16 ; year:2018 ; number:1 ; day:24 ; month:01

Links:	Volltext

DOI / URN:	10.1186/s12967-018-1384-z

Katalog-ID:	SPR028966112

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520			\|a Background Genetic engineering of T-cells to express specific T cell receptors (TCR) has emerged as a novel strategy to treat various malignancies. More widespread utilization of these types of therapies has been somewhat constrained by the lack of closed culture processes capable of expanding sufficient numbers of T-cells for clinical application. Here, we evaluate a process for robust clinical grade manufacturing of TCR gene engineered T-cells. Methods TCRs that target human papillomavirus E6 and E7 were independently tested. A 21 day process was divided into a transduction phase (7 days) and a rapid expansion phase (14 days). This process was evaluated using two healthy donor samples and four samples obtained from patients with epithelial cancers. Results The process resulted in ~ 2000-fold increase in viable nucleated cells and high transduction efficiencies (64–92%). At the end of culture, functional assays demonstrated that these cells were potent and specific in their ability to kill tumor cells bearing target and secrete large quantities of interferon and tumor necrosis factor. Both phases of culture were contained within closed or semi-closed modules, which include automated density gradient separation and cell culture bags for the first phase and closed GREX culture devices and wash/concentrate systems for the second phase. Conclusion Large-scale manufacturing using modular systems and semi-automated devices resulted in highly functional clinical-grade TCR transduced T-cells. This process is now in use in actively accruing clinical trials and the NIH Clinical Center and can be utilized at other cell therapy manufacturing sites that wish to scale-up and optimize their processing using closed systems.
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allfields	10.1186/s12967-018-1384-z doi (DE-627)SPR028966112 (SPR)s12967-018-1384-z-e DE-627 ger DE-627 rakwb eng Jin, Jianjian verfasserin aut Enhanced clinical-scale manufacturing of TCR transduced T-cells using closed culture system modules 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2018 Background Genetic engineering of T-cells to express specific T cell receptors (TCR) has emerged as a novel strategy to treat various malignancies. More widespread utilization of these types of therapies has been somewhat constrained by the lack of closed culture processes capable of expanding sufficient numbers of T-cells for clinical application. Here, we evaluate a process for robust clinical grade manufacturing of TCR gene engineered T-cells. Methods TCRs that target human papillomavirus E6 and E7 were independently tested. A 21 day process was divided into a transduction phase (7 days) and a rapid expansion phase (14 days). This process was evaluated using two healthy donor samples and four samples obtained from patients with epithelial cancers. Results The process resulted in ~ 2000-fold increase in viable nucleated cells and high transduction efficiencies (64–92%). At the end of culture, functional assays demonstrated that these cells were potent and specific in their ability to kill tumor cells bearing target and secrete large quantities of interferon and tumor necrosis factor. Both phases of culture were contained within closed or semi-closed modules, which include automated density gradient separation and cell culture bags for the first phase and closed GREX culture devices and wash/concentrate systems for the second phase. Conclusion Large-scale manufacturing using modular systems and semi-automated devices resulted in highly functional clinical-grade TCR transduced T-cells. This process is now in use in actively accruing clinical trials and the NIH Clinical Center and can be utilized at other cell therapy manufacturing sites that wish to scale-up and optimize their processing using closed systems. E6 HPV (dpeaa)DE-He213 E7 HPV (dpeaa)DE-He213 HPV-16+ (dpeaa)DE-He213 T-cell receptor (dpeaa)DE-He213 Cellular therapy (dpeaa)DE-He213 Cancer immunotherapy (dpeaa)DE-He213 Cervical cancer (dpeaa)DE-He213 Epithelial cancer (dpeaa)DE-He213 T-cell manufacturing (dpeaa)DE-He213 Gkitsas, Nikolaos aut Fellowes, Vicki S. aut Ren, Jiaqiang aut Feldman, Steven A. aut Hinrichs, Christian S. aut Stroncek, David F. aut Highfill, Steven L. (orcid)0000-0003-0135-0961 aut Enthalten in Journal of translational medicine London : BioMed Central, 2003 16(2018), 1 vom: 24. Jan. (DE-627)369084136 (DE-600)2118570-0 1479-5876 nnns volume:16 year:2018 number:1 day:24 month:01 https://dx.doi.org/10.1186/s12967-018-1384-z kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 16 2018 1 24 01
spelling	10.1186/s12967-018-1384-z doi (DE-627)SPR028966112 (SPR)s12967-018-1384-z-e DE-627 ger DE-627 rakwb eng Jin, Jianjian verfasserin aut Enhanced clinical-scale manufacturing of TCR transduced T-cells using closed culture system modules 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2018 Background Genetic engineering of T-cells to express specific T cell receptors (TCR) has emerged as a novel strategy to treat various malignancies. More widespread utilization of these types of therapies has been somewhat constrained by the lack of closed culture processes capable of expanding sufficient numbers of T-cells for clinical application. Here, we evaluate a process for robust clinical grade manufacturing of TCR gene engineered T-cells. Methods TCRs that target human papillomavirus E6 and E7 were independently tested. A 21 day process was divided into a transduction phase (7 days) and a rapid expansion phase (14 days). This process was evaluated using two healthy donor samples and four samples obtained from patients with epithelial cancers. Results The process resulted in ~ 2000-fold increase in viable nucleated cells and high transduction efficiencies (64–92%). At the end of culture, functional assays demonstrated that these cells were potent and specific in their ability to kill tumor cells bearing target and secrete large quantities of interferon and tumor necrosis factor. Both phases of culture were contained within closed or semi-closed modules, which include automated density gradient separation and cell culture bags for the first phase and closed GREX culture devices and wash/concentrate systems for the second phase. Conclusion Large-scale manufacturing using modular systems and semi-automated devices resulted in highly functional clinical-grade TCR transduced T-cells. This process is now in use in actively accruing clinical trials and the NIH Clinical Center and can be utilized at other cell therapy manufacturing sites that wish to scale-up and optimize their processing using closed systems. E6 HPV (dpeaa)DE-He213 E7 HPV (dpeaa)DE-He213 HPV-16+ (dpeaa)DE-He213 T-cell receptor (dpeaa)DE-He213 Cellular therapy (dpeaa)DE-He213 Cancer immunotherapy (dpeaa)DE-He213 Cervical cancer (dpeaa)DE-He213 Epithelial cancer (dpeaa)DE-He213 T-cell manufacturing (dpeaa)DE-He213 Gkitsas, Nikolaos aut Fellowes, Vicki S. aut Ren, Jiaqiang aut Feldman, Steven A. aut Hinrichs, Christian S. aut Stroncek, David F. aut Highfill, Steven L. (orcid)0000-0003-0135-0961 aut Enthalten in Journal of translational medicine London : BioMed Central, 2003 16(2018), 1 vom: 24. Jan. (DE-627)369084136 (DE-600)2118570-0 1479-5876 nnns volume:16 year:2018 number:1 day:24 month:01 https://dx.doi.org/10.1186/s12967-018-1384-z kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 16 2018 1 24 01
allfields_unstemmed	10.1186/s12967-018-1384-z doi (DE-627)SPR028966112 (SPR)s12967-018-1384-z-e DE-627 ger DE-627 rakwb eng Jin, Jianjian verfasserin aut Enhanced clinical-scale manufacturing of TCR transduced T-cells using closed culture system modules 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2018 Background Genetic engineering of T-cells to express specific T cell receptors (TCR) has emerged as a novel strategy to treat various malignancies. More widespread utilization of these types of therapies has been somewhat constrained by the lack of closed culture processes capable of expanding sufficient numbers of T-cells for clinical application. Here, we evaluate a process for robust clinical grade manufacturing of TCR gene engineered T-cells. Methods TCRs that target human papillomavirus E6 and E7 were independently tested. A 21 day process was divided into a transduction phase (7 days) and a rapid expansion phase (14 days). This process was evaluated using two healthy donor samples and four samples obtained from patients with epithelial cancers. Results The process resulted in ~ 2000-fold increase in viable nucleated cells and high transduction efficiencies (64–92%). At the end of culture, functional assays demonstrated that these cells were potent and specific in their ability to kill tumor cells bearing target and secrete large quantities of interferon and tumor necrosis factor. Both phases of culture were contained within closed or semi-closed modules, which include automated density gradient separation and cell culture bags for the first phase and closed GREX culture devices and wash/concentrate systems for the second phase. Conclusion Large-scale manufacturing using modular systems and semi-automated devices resulted in highly functional clinical-grade TCR transduced T-cells. This process is now in use in actively accruing clinical trials and the NIH Clinical Center and can be utilized at other cell therapy manufacturing sites that wish to scale-up and optimize their processing using closed systems. E6 HPV (dpeaa)DE-He213 E7 HPV (dpeaa)DE-He213 HPV-16+ (dpeaa)DE-He213 T-cell receptor (dpeaa)DE-He213 Cellular therapy (dpeaa)DE-He213 Cancer immunotherapy (dpeaa)DE-He213 Cervical cancer (dpeaa)DE-He213 Epithelial cancer (dpeaa)DE-He213 T-cell manufacturing (dpeaa)DE-He213 Gkitsas, Nikolaos aut Fellowes, Vicki S. aut Ren, Jiaqiang aut Feldman, Steven A. aut Hinrichs, Christian S. aut Stroncek, David F. aut Highfill, Steven L. (orcid)0000-0003-0135-0961 aut Enthalten in Journal of translational medicine London : BioMed Central, 2003 16(2018), 1 vom: 24. Jan. (DE-627)369084136 (DE-600)2118570-0 1479-5876 nnns volume:16 year:2018 number:1 day:24 month:01 https://dx.doi.org/10.1186/s12967-018-1384-z kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 16 2018 1 24 01
allfieldsGer	10.1186/s12967-018-1384-z doi (DE-627)SPR028966112 (SPR)s12967-018-1384-z-e DE-627 ger DE-627 rakwb eng Jin, Jianjian verfasserin aut Enhanced clinical-scale manufacturing of TCR transduced T-cells using closed culture system modules 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2018 Background Genetic engineering of T-cells to express specific T cell receptors (TCR) has emerged as a novel strategy to treat various malignancies. More widespread utilization of these types of therapies has been somewhat constrained by the lack of closed culture processes capable of expanding sufficient numbers of T-cells for clinical application. Here, we evaluate a process for robust clinical grade manufacturing of TCR gene engineered T-cells. Methods TCRs that target human papillomavirus E6 and E7 were independently tested. A 21 day process was divided into a transduction phase (7 days) and a rapid expansion phase (14 days). This process was evaluated using two healthy donor samples and four samples obtained from patients with epithelial cancers. Results The process resulted in ~ 2000-fold increase in viable nucleated cells and high transduction efficiencies (64–92%). At the end of culture, functional assays demonstrated that these cells were potent and specific in their ability to kill tumor cells bearing target and secrete large quantities of interferon and tumor necrosis factor. Both phases of culture were contained within closed or semi-closed modules, which include automated density gradient separation and cell culture bags for the first phase and closed GREX culture devices and wash/concentrate systems for the second phase. Conclusion Large-scale manufacturing using modular systems and semi-automated devices resulted in highly functional clinical-grade TCR transduced T-cells. This process is now in use in actively accruing clinical trials and the NIH Clinical Center and can be utilized at other cell therapy manufacturing sites that wish to scale-up and optimize their processing using closed systems. E6 HPV (dpeaa)DE-He213 E7 HPV (dpeaa)DE-He213 HPV-16+ (dpeaa)DE-He213 T-cell receptor (dpeaa)DE-He213 Cellular therapy (dpeaa)DE-He213 Cancer immunotherapy (dpeaa)DE-He213 Cervical cancer (dpeaa)DE-He213 Epithelial cancer (dpeaa)DE-He213 T-cell manufacturing (dpeaa)DE-He213 Gkitsas, Nikolaos aut Fellowes, Vicki S. aut Ren, Jiaqiang aut Feldman, Steven A. aut Hinrichs, Christian S. aut Stroncek, David F. aut Highfill, Steven L. (orcid)0000-0003-0135-0961 aut Enthalten in Journal of translational medicine London : BioMed Central, 2003 16(2018), 1 vom: 24. Jan. (DE-627)369084136 (DE-600)2118570-0 1479-5876 nnns volume:16 year:2018 number:1 day:24 month:01 https://dx.doi.org/10.1186/s12967-018-1384-z kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 16 2018 1 24 01
allfieldsSound	10.1186/s12967-018-1384-z doi (DE-627)SPR028966112 (SPR)s12967-018-1384-z-e DE-627 ger DE-627 rakwb eng Jin, Jianjian verfasserin aut Enhanced clinical-scale manufacturing of TCR transduced T-cells using closed culture system modules 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2018 Background Genetic engineering of T-cells to express specific T cell receptors (TCR) has emerged as a novel strategy to treat various malignancies. More widespread utilization of these types of therapies has been somewhat constrained by the lack of closed culture processes capable of expanding sufficient numbers of T-cells for clinical application. Here, we evaluate a process for robust clinical grade manufacturing of TCR gene engineered T-cells. Methods TCRs that target human papillomavirus E6 and E7 were independently tested. A 21 day process was divided into a transduction phase (7 days) and a rapid expansion phase (14 days). This process was evaluated using two healthy donor samples and four samples obtained from patients with epithelial cancers. Results The process resulted in ~ 2000-fold increase in viable nucleated cells and high transduction efficiencies (64–92%). At the end of culture, functional assays demonstrated that these cells were potent and specific in their ability to kill tumor cells bearing target and secrete large quantities of interferon and tumor necrosis factor. Both phases of culture were contained within closed or semi-closed modules, which include automated density gradient separation and cell culture bags for the first phase and closed GREX culture devices and wash/concentrate systems for the second phase. Conclusion Large-scale manufacturing using modular systems and semi-automated devices resulted in highly functional clinical-grade TCR transduced T-cells. This process is now in use in actively accruing clinical trials and the NIH Clinical Center and can be utilized at other cell therapy manufacturing sites that wish to scale-up and optimize their processing using closed systems. E6 HPV (dpeaa)DE-He213 E7 HPV (dpeaa)DE-He213 HPV-16+ (dpeaa)DE-He213 T-cell receptor (dpeaa)DE-He213 Cellular therapy (dpeaa)DE-He213 Cancer immunotherapy (dpeaa)DE-He213 Cervical cancer (dpeaa)DE-He213 Epithelial cancer (dpeaa)DE-He213 T-cell manufacturing (dpeaa)DE-He213 Gkitsas, Nikolaos aut Fellowes, Vicki S. aut Ren, Jiaqiang aut Feldman, Steven A. aut Hinrichs, Christian S. aut Stroncek, David F. aut Highfill, Steven L. (orcid)0000-0003-0135-0961 aut Enthalten in Journal of translational medicine London : BioMed Central, 2003 16(2018), 1 vom: 24. Jan. (DE-627)369084136 (DE-600)2118570-0 1479-5876 nnns volume:16 year:2018 number:1 day:24 month:01 https://dx.doi.org/10.1186/s12967-018-1384-z kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 16 2018 1 24 01
language	English
source	Enthalten in Journal of translational medicine 16(2018), 1 vom: 24. Jan. volume:16 year:2018 number:1 day:24 month:01
sourceStr	Enthalten in Journal of translational medicine 16(2018), 1 vom: 24. Jan. volume:16 year:2018 number:1 day:24 month:01
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topic_facet	E6 HPV E7 HPV HPV-16+ T-cell receptor Cellular therapy Cancer immunotherapy Cervical cancer Epithelial cancer T-cell manufacturing
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authorswithroles_txt_mv	Jin, Jianjian @@aut@@ Gkitsas, Nikolaos @@aut@@ Fellowes, Vicki S. @@aut@@ Ren, Jiaqiang @@aut@@ Feldman, Steven A. @@aut@@ Hinrichs, Christian S. @@aut@@ Stroncek, David F. @@aut@@ Highfill, Steven L. @@aut@@
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author	Jin, Jianjian
spellingShingle	Jin, Jianjian misc E6 HPV misc E7 HPV misc HPV-16+ misc T-cell receptor misc Cellular therapy misc Cancer immunotherapy misc Cervical cancer misc Epithelial cancer misc T-cell manufacturing Enhanced clinical-scale manufacturing of TCR transduced T-cells using closed culture system modules
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topic_title	Enhanced clinical-scale manufacturing of TCR transduced T-cells using closed culture system modules E6 HPV (dpeaa)DE-He213 E7 HPV (dpeaa)DE-He213 HPV-16+ (dpeaa)DE-He213 T-cell receptor (dpeaa)DE-He213 Cellular therapy (dpeaa)DE-He213 Cancer immunotherapy (dpeaa)DE-He213 Cervical cancer (dpeaa)DE-He213 Epithelial cancer (dpeaa)DE-He213 T-cell manufacturing (dpeaa)DE-He213
topic	misc E6 HPV misc E7 HPV misc HPV-16+ misc T-cell receptor misc Cellular therapy misc Cancer immunotherapy misc Cervical cancer misc Epithelial cancer misc T-cell manufacturing
topic_unstemmed	misc E6 HPV misc E7 HPV misc HPV-16+ misc T-cell receptor misc Cellular therapy misc Cancer immunotherapy misc Cervical cancer misc Epithelial cancer misc T-cell manufacturing
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title	Enhanced clinical-scale manufacturing of TCR transduced T-cells using closed culture system modules
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title_full	Enhanced clinical-scale manufacturing of TCR transduced T-cells using closed culture system modules
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title_sort	enhanced clinical-scale manufacturing of tcr transduced t-cells using closed culture system modules
title_auth	Enhanced clinical-scale manufacturing of TCR transduced T-cells using closed culture system modules
abstract	Background Genetic engineering of T-cells to express specific T cell receptors (TCR) has emerged as a novel strategy to treat various malignancies. More widespread utilization of these types of therapies has been somewhat constrained by the lack of closed culture processes capable of expanding sufficient numbers of T-cells for clinical application. Here, we evaluate a process for robust clinical grade manufacturing of TCR gene engineered T-cells. Methods TCRs that target human papillomavirus E6 and E7 were independently tested. A 21 day process was divided into a transduction phase (7 days) and a rapid expansion phase (14 days). This process was evaluated using two healthy donor samples and four samples obtained from patients with epithelial cancers. Results The process resulted in ~ 2000-fold increase in viable nucleated cells and high transduction efficiencies (64–92%). At the end of culture, functional assays demonstrated that these cells were potent and specific in their ability to kill tumor cells bearing target and secrete large quantities of interferon and tumor necrosis factor. Both phases of culture were contained within closed or semi-closed modules, which include automated density gradient separation and cell culture bags for the first phase and closed GREX culture devices and wash/concentrate systems for the second phase. Conclusion Large-scale manufacturing using modular systems and semi-automated devices resulted in highly functional clinical-grade TCR transduced T-cells. This process is now in use in actively accruing clinical trials and the NIH Clinical Center and can be utilized at other cell therapy manufacturing sites that wish to scale-up and optimize their processing using closed systems. © The Author(s) 2018
abstractGer	Background Genetic engineering of T-cells to express specific T cell receptors (TCR) has emerged as a novel strategy to treat various malignancies. More widespread utilization of these types of therapies has been somewhat constrained by the lack of closed culture processes capable of expanding sufficient numbers of T-cells for clinical application. Here, we evaluate a process for robust clinical grade manufacturing of TCR gene engineered T-cells. Methods TCRs that target human papillomavirus E6 and E7 were independently tested. A 21 day process was divided into a transduction phase (7 days) and a rapid expansion phase (14 days). This process was evaluated using two healthy donor samples and four samples obtained from patients with epithelial cancers. Results The process resulted in ~ 2000-fold increase in viable nucleated cells and high transduction efficiencies (64–92%). At the end of culture, functional assays demonstrated that these cells were potent and specific in their ability to kill tumor cells bearing target and secrete large quantities of interferon and tumor necrosis factor. Both phases of culture were contained within closed or semi-closed modules, which include automated density gradient separation and cell culture bags for the first phase and closed GREX culture devices and wash/concentrate systems for the second phase. Conclusion Large-scale manufacturing using modular systems and semi-automated devices resulted in highly functional clinical-grade TCR transduced T-cells. This process is now in use in actively accruing clinical trials and the NIH Clinical Center and can be utilized at other cell therapy manufacturing sites that wish to scale-up and optimize their processing using closed systems. © The Author(s) 2018
abstract_unstemmed	Background Genetic engineering of T-cells to express specific T cell receptors (TCR) has emerged as a novel strategy to treat various malignancies. More widespread utilization of these types of therapies has been somewhat constrained by the lack of closed culture processes capable of expanding sufficient numbers of T-cells for clinical application. Here, we evaluate a process for robust clinical grade manufacturing of TCR gene engineered T-cells. Methods TCRs that target human papillomavirus E6 and E7 were independently tested. A 21 day process was divided into a transduction phase (7 days) and a rapid expansion phase (14 days). This process was evaluated using two healthy donor samples and four samples obtained from patients with epithelial cancers. Results The process resulted in ~ 2000-fold increase in viable nucleated cells and high transduction efficiencies (64–92%). At the end of culture, functional assays demonstrated that these cells were potent and specific in their ability to kill tumor cells bearing target and secrete large quantities of interferon and tumor necrosis factor. Both phases of culture were contained within closed or semi-closed modules, which include automated density gradient separation and cell culture bags for the first phase and closed GREX culture devices and wash/concentrate systems for the second phase. Conclusion Large-scale manufacturing using modular systems and semi-automated devices resulted in highly functional clinical-grade TCR transduced T-cells. This process is now in use in actively accruing clinical trials and the NIH Clinical Center and can be utilized at other cell therapy manufacturing sites that wish to scale-up and optimize their processing using closed systems. © The Author(s) 2018
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title_short	Enhanced clinical-scale manufacturing of TCR transduced T-cells using closed culture system modules
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author2	Gkitsas, Nikolaos Fellowes, Vicki S. Ren, Jiaqiang Feldman, Steven A. Hinrichs, Christian S. Stroncek, David F. Highfill, Steven L.
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More widespread utilization of these types of therapies has been somewhat constrained by the lack of closed culture processes capable of expanding sufficient numbers of T-cells for clinical application. Here, we evaluate a process for robust clinical grade manufacturing of TCR gene engineered T-cells. Methods TCRs that target human papillomavirus E6 and E7 were independently tested. A 21 day process was divided into a transduction phase (7 days) and a rapid expansion phase (14 days). This process was evaluated using two healthy donor samples and four samples obtained from patients with epithelial cancers. Results The process resulted in ~ 2000-fold increase in viable nucleated cells and high transduction efficiencies (64–92%). At the end of culture, functional assays demonstrated that these cells were potent and specific in their ability to kill tumor cells bearing target and secrete large quantities of interferon and tumor necrosis factor. Both phases of culture were contained within closed or semi-closed modules, which include automated density gradient separation and cell culture bags for the first phase and closed GREX culture devices and wash/concentrate systems for the second phase. Conclusion Large-scale manufacturing using modular systems and semi-automated devices resulted in highly functional clinical-grade TCR transduced T-cells. 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Enhanced clinical-scale manufacturing of TCR transduced T-cells using closed culture system modules

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