Targeting the TGFβ pathway with galunisertib, a TGFβRI small molecule inhibitor, promotes anti-tumor immunity leading to durable, complete responses, as monotherapy and in combination with checkpoint blockade

Background TGFβ signaling plays a pleotropic role in tumor biology, promoting tumor proliferation, invasion and metastasis, and escape from immune surveillance. Inhibiting TGFβ’s immune suppressive effects has become of particular interest as a way to increase the benefit of cancer immunotherapy. He...
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Autor*in:	Holmgaard, Rikke B. [verfasserIn] Schaer, David A. Li, Yanxia Castaneda, Stephen P. Murphy, Mary Y. Xu, Xiaohong Inigo, Ivan Dobkin, Julie Manro, Jason R. Iversen, Philip W. Surguladze, David Hall, Gerald E. Novosiadly, Ruslan D. Benhadji, Karim A. Plowman, Gregory D. Kalos, Michael Driscoll, Kyla E.

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2018

Schlagwörter:	TGF-β receptor I Antitumor efficacy Checkpoint inhibitors Galunisertib

Anmerkung:	© The Author(s). 2018

Übergeordnetes Werk:	Enthalten in: Journal for ImmunoTherapy of Cancer - London : BioMed Central, 2013, 6(2018), 1 vom: 04. Juni
Übergeordnetes Werk:	volume:6 ; year:2018 ; number:1 ; day:04 ; month:06

Links:	Volltext

DOI / URN:	10.1186/s40425-018-0356-4

Katalog-ID:	SPR036436917

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520			\|a Background TGFβ signaling plays a pleotropic role in tumor biology, promoting tumor proliferation, invasion and metastasis, and escape from immune surveillance. Inhibiting TGFβ’s immune suppressive effects has become of particular interest as a way to increase the benefit of cancer immunotherapy. Here we utilized preclinical models to explore the impact of the clinical stage TGFβ pathway inhibitor, galunisertib, on anti-tumor immunity at clinically relevant doses. Results In vitro treatment with galunisertib reversed TGFβ and regulatory T cell mediated suppression of human T cell proliferation. In vivo treatment of mice with established 4T1-LP tumors resulted in strong dose-dependent anti-tumor activity with close to 100% inhibition of tumor growth and complete regressions upon cessation of treatment in 50% of animals. This effect was CD8+ T cell dependent, and led to increased T cell numbers in treated tumors. Mice with durable regressions rejected tumor rechallenge, demonstrating the establishment of immunological memory. Consequently, mice that rejected immunogenic 4T1-LP tumors were able to resist rechallenge with poorly immunogenic 4 T1 parental cells, suggesting the development of a secondary immune response via antigen spreading as a consequence of effective tumor targeting. Combination of galunisertib with PD-L1 blockade resulted in improved tumor growth inhibition and complete regressions in colon carcinoma models, demonstrating the potential synergy when cotargeting TGFβ and PD-1/PD-L1 pathways. Combination therapy was associated with enhanced anti-tumor immune related gene expression profile that was accelerated compared to anti-PD-L1 monotherapy. Conclusions Together these data highlight the ability of galunisertib to modulate T cell immunity and the therapeutic potential of combining galunisertib with current PD-1/L1 immunotherapy.
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allfields	10.1186/s40425-018-0356-4 doi (DE-627)SPR036436917 (SPR)s40425-018-0356-4-e DE-627 ger DE-627 rakwb eng Holmgaard, Rikke B. verfasserin aut Targeting the TGFβ pathway with galunisertib, a TGFβRI small molecule inhibitor, promotes anti-tumor immunity leading to durable, complete responses, as monotherapy and in combination with checkpoint blockade 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s). 2018 Background TGFβ signaling plays a pleotropic role in tumor biology, promoting tumor proliferation, invasion and metastasis, and escape from immune surveillance. Inhibiting TGFβ’s immune suppressive effects has become of particular interest as a way to increase the benefit of cancer immunotherapy. Here we utilized preclinical models to explore the impact of the clinical stage TGFβ pathway inhibitor, galunisertib, on anti-tumor immunity at clinically relevant doses. Results In vitro treatment with galunisertib reversed TGFβ and regulatory T cell mediated suppression of human T cell proliferation. In vivo treatment of mice with established 4T1-LP tumors resulted in strong dose-dependent anti-tumor activity with close to 100% inhibition of tumor growth and complete regressions upon cessation of treatment in 50% of animals. This effect was CD8+ T cell dependent, and led to increased T cell numbers in treated tumors. Mice with durable regressions rejected tumor rechallenge, demonstrating the establishment of immunological memory. Consequently, mice that rejected immunogenic 4T1-LP tumors were able to resist rechallenge with poorly immunogenic 4 T1 parental cells, suggesting the development of a secondary immune response via antigen spreading as a consequence of effective tumor targeting. Combination of galunisertib with PD-L1 blockade resulted in improved tumor growth inhibition and complete regressions in colon carcinoma models, demonstrating the potential synergy when cotargeting TGFβ and PD-1/PD-L1 pathways. Combination therapy was associated with enhanced anti-tumor immune related gene expression profile that was accelerated compared to anti-PD-L1 monotherapy. Conclusions Together these data highlight the ability of galunisertib to modulate T cell immunity and the therapeutic potential of combining galunisertib with current PD-1/L1 immunotherapy. TGF-β receptor I (dpeaa)DE-He213 Antitumor efficacy (dpeaa)DE-He213 Checkpoint inhibitors (dpeaa)DE-He213 Galunisertib (dpeaa)DE-He213 Schaer, David A. aut Li, Yanxia aut Castaneda, Stephen P. aut Murphy, Mary Y. aut Xu, Xiaohong aut Inigo, Ivan aut Dobkin, Julie aut Manro, Jason R. aut Iversen, Philip W. aut Surguladze, David aut Hall, Gerald E. aut Novosiadly, Ruslan D. aut Benhadji, Karim A. aut Plowman, Gregory D. aut Kalos, Michael aut Driscoll, Kyla E. aut Enthalten in Journal for ImmunoTherapy of Cancer London : BioMed Central, 2013 6(2018), 1 vom: 04. Juni (DE-627)750086335 (DE-600)2719863-7 2051-1426 nnns volume:6 year:2018 number:1 day:04 month:06 https://dx.doi.org/10.1186/s40425-018-0356-4 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_2014 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 6 2018 1 04 06
spelling	10.1186/s40425-018-0356-4 doi (DE-627)SPR036436917 (SPR)s40425-018-0356-4-e DE-627 ger DE-627 rakwb eng Holmgaard, Rikke B. verfasserin aut Targeting the TGFβ pathway with galunisertib, a TGFβRI small molecule inhibitor, promotes anti-tumor immunity leading to durable, complete responses, as monotherapy and in combination with checkpoint blockade 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s). 2018 Background TGFβ signaling plays a pleotropic role in tumor biology, promoting tumor proliferation, invasion and metastasis, and escape from immune surveillance. Inhibiting TGFβ’s immune suppressive effects has become of particular interest as a way to increase the benefit of cancer immunotherapy. Here we utilized preclinical models to explore the impact of the clinical stage TGFβ pathway inhibitor, galunisertib, on anti-tumor immunity at clinically relevant doses. Results In vitro treatment with galunisertib reversed TGFβ and regulatory T cell mediated suppression of human T cell proliferation. In vivo treatment of mice with established 4T1-LP tumors resulted in strong dose-dependent anti-tumor activity with close to 100% inhibition of tumor growth and complete regressions upon cessation of treatment in 50% of animals. This effect was CD8+ T cell dependent, and led to increased T cell numbers in treated tumors. Mice with durable regressions rejected tumor rechallenge, demonstrating the establishment of immunological memory. Consequently, mice that rejected immunogenic 4T1-LP tumors were able to resist rechallenge with poorly immunogenic 4 T1 parental cells, suggesting the development of a secondary immune response via antigen spreading as a consequence of effective tumor targeting. Combination of galunisertib with PD-L1 blockade resulted in improved tumor growth inhibition and complete regressions in colon carcinoma models, demonstrating the potential synergy when cotargeting TGFβ and PD-1/PD-L1 pathways. Combination therapy was associated with enhanced anti-tumor immune related gene expression profile that was accelerated compared to anti-PD-L1 monotherapy. Conclusions Together these data highlight the ability of galunisertib to modulate T cell immunity and the therapeutic potential of combining galunisertib with current PD-1/L1 immunotherapy. TGF-β receptor I (dpeaa)DE-He213 Antitumor efficacy (dpeaa)DE-He213 Checkpoint inhibitors (dpeaa)DE-He213 Galunisertib (dpeaa)DE-He213 Schaer, David A. aut Li, Yanxia aut Castaneda, Stephen P. aut Murphy, Mary Y. aut Xu, Xiaohong aut Inigo, Ivan aut Dobkin, Julie aut Manro, Jason R. aut Iversen, Philip W. aut Surguladze, David aut Hall, Gerald E. aut Novosiadly, Ruslan D. aut Benhadji, Karim A. aut Plowman, Gregory D. aut Kalos, Michael aut Driscoll, Kyla E. aut Enthalten in Journal for ImmunoTherapy of Cancer London : BioMed Central, 2013 6(2018), 1 vom: 04. Juni (DE-627)750086335 (DE-600)2719863-7 2051-1426 nnns volume:6 year:2018 number:1 day:04 month:06 https://dx.doi.org/10.1186/s40425-018-0356-4 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_2014 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 6 2018 1 04 06
allfields_unstemmed	10.1186/s40425-018-0356-4 doi (DE-627)SPR036436917 (SPR)s40425-018-0356-4-e DE-627 ger DE-627 rakwb eng Holmgaard, Rikke B. verfasserin aut Targeting the TGFβ pathway with galunisertib, a TGFβRI small molecule inhibitor, promotes anti-tumor immunity leading to durable, complete responses, as monotherapy and in combination with checkpoint blockade 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s). 2018 Background TGFβ signaling plays a pleotropic role in tumor biology, promoting tumor proliferation, invasion and metastasis, and escape from immune surveillance. Inhibiting TGFβ’s immune suppressive effects has become of particular interest as a way to increase the benefit of cancer immunotherapy. Here we utilized preclinical models to explore the impact of the clinical stage TGFβ pathway inhibitor, galunisertib, on anti-tumor immunity at clinically relevant doses. Results In vitro treatment with galunisertib reversed TGFβ and regulatory T cell mediated suppression of human T cell proliferation. In vivo treatment of mice with established 4T1-LP tumors resulted in strong dose-dependent anti-tumor activity with close to 100% inhibition of tumor growth and complete regressions upon cessation of treatment in 50% of animals. This effect was CD8+ T cell dependent, and led to increased T cell numbers in treated tumors. Mice with durable regressions rejected tumor rechallenge, demonstrating the establishment of immunological memory. Consequently, mice that rejected immunogenic 4T1-LP tumors were able to resist rechallenge with poorly immunogenic 4 T1 parental cells, suggesting the development of a secondary immune response via antigen spreading as a consequence of effective tumor targeting. Combination of galunisertib with PD-L1 blockade resulted in improved tumor growth inhibition and complete regressions in colon carcinoma models, demonstrating the potential synergy when cotargeting TGFβ and PD-1/PD-L1 pathways. Combination therapy was associated with enhanced anti-tumor immune related gene expression profile that was accelerated compared to anti-PD-L1 monotherapy. Conclusions Together these data highlight the ability of galunisertib to modulate T cell immunity and the therapeutic potential of combining galunisertib with current PD-1/L1 immunotherapy. TGF-β receptor I (dpeaa)DE-He213 Antitumor efficacy (dpeaa)DE-He213 Checkpoint inhibitors (dpeaa)DE-He213 Galunisertib (dpeaa)DE-He213 Schaer, David A. aut Li, Yanxia aut Castaneda, Stephen P. aut Murphy, Mary Y. aut Xu, Xiaohong aut Inigo, Ivan aut Dobkin, Julie aut Manro, Jason R. aut Iversen, Philip W. aut Surguladze, David aut Hall, Gerald E. aut Novosiadly, Ruslan D. aut Benhadji, Karim A. aut Plowman, Gregory D. aut Kalos, Michael aut Driscoll, Kyla E. aut Enthalten in Journal for ImmunoTherapy of Cancer London : BioMed Central, 2013 6(2018), 1 vom: 04. Juni (DE-627)750086335 (DE-600)2719863-7 2051-1426 nnns volume:6 year:2018 number:1 day:04 month:06 https://dx.doi.org/10.1186/s40425-018-0356-4 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_2014 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 6 2018 1 04 06
allfieldsGer	10.1186/s40425-018-0356-4 doi (DE-627)SPR036436917 (SPR)s40425-018-0356-4-e DE-627 ger DE-627 rakwb eng Holmgaard, Rikke B. verfasserin aut Targeting the TGFβ pathway with galunisertib, a TGFβRI small molecule inhibitor, promotes anti-tumor immunity leading to durable, complete responses, as monotherapy and in combination with checkpoint blockade 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s). 2018 Background TGFβ signaling plays a pleotropic role in tumor biology, promoting tumor proliferation, invasion and metastasis, and escape from immune surveillance. Inhibiting TGFβ’s immune suppressive effects has become of particular interest as a way to increase the benefit of cancer immunotherapy. Here we utilized preclinical models to explore the impact of the clinical stage TGFβ pathway inhibitor, galunisertib, on anti-tumor immunity at clinically relevant doses. Results In vitro treatment with galunisertib reversed TGFβ and regulatory T cell mediated suppression of human T cell proliferation. In vivo treatment of mice with established 4T1-LP tumors resulted in strong dose-dependent anti-tumor activity with close to 100% inhibition of tumor growth and complete regressions upon cessation of treatment in 50% of animals. This effect was CD8+ T cell dependent, and led to increased T cell numbers in treated tumors. Mice with durable regressions rejected tumor rechallenge, demonstrating the establishment of immunological memory. Consequently, mice that rejected immunogenic 4T1-LP tumors were able to resist rechallenge with poorly immunogenic 4 T1 parental cells, suggesting the development of a secondary immune response via antigen spreading as a consequence of effective tumor targeting. Combination of galunisertib with PD-L1 blockade resulted in improved tumor growth inhibition and complete regressions in colon carcinoma models, demonstrating the potential synergy when cotargeting TGFβ and PD-1/PD-L1 pathways. Combination therapy was associated with enhanced anti-tumor immune related gene expression profile that was accelerated compared to anti-PD-L1 monotherapy. Conclusions Together these data highlight the ability of galunisertib to modulate T cell immunity and the therapeutic potential of combining galunisertib with current PD-1/L1 immunotherapy. TGF-β receptor I (dpeaa)DE-He213 Antitumor efficacy (dpeaa)DE-He213 Checkpoint inhibitors (dpeaa)DE-He213 Galunisertib (dpeaa)DE-He213 Schaer, David A. aut Li, Yanxia aut Castaneda, Stephen P. aut Murphy, Mary Y. aut Xu, Xiaohong aut Inigo, Ivan aut Dobkin, Julie aut Manro, Jason R. aut Iversen, Philip W. aut Surguladze, David aut Hall, Gerald E. aut Novosiadly, Ruslan D. aut Benhadji, Karim A. aut Plowman, Gregory D. aut Kalos, Michael aut Driscoll, Kyla E. aut Enthalten in Journal for ImmunoTherapy of Cancer London : BioMed Central, 2013 6(2018), 1 vom: 04. Juni (DE-627)750086335 (DE-600)2719863-7 2051-1426 nnns volume:6 year:2018 number:1 day:04 month:06 https://dx.doi.org/10.1186/s40425-018-0356-4 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_2014 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 6 2018 1 04 06
allfieldsSound	10.1186/s40425-018-0356-4 doi (DE-627)SPR036436917 (SPR)s40425-018-0356-4-e DE-627 ger DE-627 rakwb eng Holmgaard, Rikke B. verfasserin aut Targeting the TGFβ pathway with galunisertib, a TGFβRI small molecule inhibitor, promotes anti-tumor immunity leading to durable, complete responses, as monotherapy and in combination with checkpoint blockade 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s). 2018 Background TGFβ signaling plays a pleotropic role in tumor biology, promoting tumor proliferation, invasion and metastasis, and escape from immune surveillance. Inhibiting TGFβ’s immune suppressive effects has become of particular interest as a way to increase the benefit of cancer immunotherapy. Here we utilized preclinical models to explore the impact of the clinical stage TGFβ pathway inhibitor, galunisertib, on anti-tumor immunity at clinically relevant doses. Results In vitro treatment with galunisertib reversed TGFβ and regulatory T cell mediated suppression of human T cell proliferation. In vivo treatment of mice with established 4T1-LP tumors resulted in strong dose-dependent anti-tumor activity with close to 100% inhibition of tumor growth and complete regressions upon cessation of treatment in 50% of animals. This effect was CD8+ T cell dependent, and led to increased T cell numbers in treated tumors. Mice with durable regressions rejected tumor rechallenge, demonstrating the establishment of immunological memory. Consequently, mice that rejected immunogenic 4T1-LP tumors were able to resist rechallenge with poorly immunogenic 4 T1 parental cells, suggesting the development of a secondary immune response via antigen spreading as a consequence of effective tumor targeting. Combination of galunisertib with PD-L1 blockade resulted in improved tumor growth inhibition and complete regressions in colon carcinoma models, demonstrating the potential synergy when cotargeting TGFβ and PD-1/PD-L1 pathways. Combination therapy was associated with enhanced anti-tumor immune related gene expression profile that was accelerated compared to anti-PD-L1 monotherapy. Conclusions Together these data highlight the ability of galunisertib to modulate T cell immunity and the therapeutic potential of combining galunisertib with current PD-1/L1 immunotherapy. TGF-β receptor I (dpeaa)DE-He213 Antitumor efficacy (dpeaa)DE-He213 Checkpoint inhibitors (dpeaa)DE-He213 Galunisertib (dpeaa)DE-He213 Schaer, David A. aut Li, Yanxia aut Castaneda, Stephen P. aut Murphy, Mary Y. aut Xu, Xiaohong aut Inigo, Ivan aut Dobkin, Julie aut Manro, Jason R. aut Iversen, Philip W. aut Surguladze, David aut Hall, Gerald E. aut Novosiadly, Ruslan D. aut Benhadji, Karim A. aut Plowman, Gregory D. aut Kalos, Michael aut Driscoll, Kyla E. aut Enthalten in Journal for ImmunoTherapy of Cancer London : BioMed Central, 2013 6(2018), 1 vom: 04. Juni (DE-627)750086335 (DE-600)2719863-7 2051-1426 nnns volume:6 year:2018 number:1 day:04 month:06 https://dx.doi.org/10.1186/s40425-018-0356-4 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_2014 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 6 2018 1 04 06
language	English
source	Enthalten in Journal for ImmunoTherapy of Cancer 6(2018), 1 vom: 04. Juni volume:6 year:2018 number:1 day:04 month:06
sourceStr	Enthalten in Journal for ImmunoTherapy of Cancer 6(2018), 1 vom: 04. Juni volume:6 year:2018 number:1 day:04 month:06
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	TGF-β receptor I Antitumor efficacy Checkpoint inhibitors Galunisertib
isfreeaccess_bool	true
container_title	Journal for ImmunoTherapy of Cancer
authorswithroles_txt_mv	Holmgaard, Rikke B. @@aut@@ Schaer, David A. @@aut@@ Li, Yanxia @@aut@@ Castaneda, Stephen P. @@aut@@ Murphy, Mary Y. @@aut@@ Xu, Xiaohong @@aut@@ Inigo, Ivan @@aut@@ Dobkin, Julie @@aut@@ Manro, Jason R. @@aut@@ Iversen, Philip W. @@aut@@ Surguladze, David @@aut@@ Hall, Gerald E. @@aut@@ Novosiadly, Ruslan D. @@aut@@ Benhadji, Karim A. @@aut@@ Plowman, Gregory D. @@aut@@ Kalos, Michael @@aut@@ Driscoll, Kyla E. @@aut@@
publishDateDaySort_date	2018-06-04T00:00:00Z
hierarchy_top_id	750086335
id	SPR036436917
language_de	englisch
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author	Holmgaard, Rikke B.
spellingShingle	Holmgaard, Rikke B. misc TGF-β receptor I misc Antitumor efficacy misc Checkpoint inhibitors misc Galunisertib Targeting the TGFβ pathway with galunisertib, a TGFβRI small molecule inhibitor, promotes anti-tumor immunity leading to durable, complete responses, as monotherapy and in combination with checkpoint blockade
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topic_title	Targeting the TGFβ pathway with galunisertib, a TGFβRI small molecule inhibitor, promotes anti-tumor immunity leading to durable, complete responses, as monotherapy and in combination with checkpoint blockade TGF-β receptor I (dpeaa)DE-He213 Antitumor efficacy (dpeaa)DE-He213 Checkpoint inhibitors (dpeaa)DE-He213 Galunisertib (dpeaa)DE-He213
topic	misc TGF-β receptor I misc Antitumor efficacy misc Checkpoint inhibitors misc Galunisertib
topic_unstemmed	misc TGF-β receptor I misc Antitumor efficacy misc Checkpoint inhibitors misc Galunisertib
topic_browse	misc TGF-β receptor I misc Antitumor efficacy misc Checkpoint inhibitors misc Galunisertib
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title	Targeting the TGFβ pathway with galunisertib, a TGFβRI small molecule inhibitor, promotes anti-tumor immunity leading to durable, complete responses, as monotherapy and in combination with checkpoint blockade
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title_full	Targeting the TGFβ pathway with galunisertib, a TGFβRI small molecule inhibitor, promotes anti-tumor immunity leading to durable, complete responses, as monotherapy and in combination with checkpoint blockade
author_sort	Holmgaard, Rikke B.
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author_browse	Holmgaard, Rikke B. Schaer, David A. Li, Yanxia Castaneda, Stephen P. Murphy, Mary Y. Xu, Xiaohong Inigo, Ivan Dobkin, Julie Manro, Jason R. Iversen, Philip W. Surguladze, David Hall, Gerald E. Novosiadly, Ruslan D. Benhadji, Karim A. Plowman, Gregory D. Kalos, Michael Driscoll, Kyla E.
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author-letter	Holmgaard, Rikke B.
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title_sort	targeting the tgfβ pathway with galunisertib, a tgfβri small molecule inhibitor, promotes anti-tumor immunity leading to durable, complete responses, as monotherapy and in combination with checkpoint blockade
title_auth	Targeting the TGFβ pathway with galunisertib, a TGFβRI small molecule inhibitor, promotes anti-tumor immunity leading to durable, complete responses, as monotherapy and in combination with checkpoint blockade
abstract	Background TGFβ signaling plays a pleotropic role in tumor biology, promoting tumor proliferation, invasion and metastasis, and escape from immune surveillance. Inhibiting TGFβ’s immune suppressive effects has become of particular interest as a way to increase the benefit of cancer immunotherapy. Here we utilized preclinical models to explore the impact of the clinical stage TGFβ pathway inhibitor, galunisertib, on anti-tumor immunity at clinically relevant doses. Results In vitro treatment with galunisertib reversed TGFβ and regulatory T cell mediated suppression of human T cell proliferation. In vivo treatment of mice with established 4T1-LP tumors resulted in strong dose-dependent anti-tumor activity with close to 100% inhibition of tumor growth and complete regressions upon cessation of treatment in 50% of animals. This effect was CD8+ T cell dependent, and led to increased T cell numbers in treated tumors. Mice with durable regressions rejected tumor rechallenge, demonstrating the establishment of immunological memory. Consequently, mice that rejected immunogenic 4T1-LP tumors were able to resist rechallenge with poorly immunogenic 4 T1 parental cells, suggesting the development of a secondary immune response via antigen spreading as a consequence of effective tumor targeting. Combination of galunisertib with PD-L1 blockade resulted in improved tumor growth inhibition and complete regressions in colon carcinoma models, demonstrating the potential synergy when cotargeting TGFβ and PD-1/PD-L1 pathways. Combination therapy was associated with enhanced anti-tumor immune related gene expression profile that was accelerated compared to anti-PD-L1 monotherapy. Conclusions Together these data highlight the ability of galunisertib to modulate T cell immunity and the therapeutic potential of combining galunisertib with current PD-1/L1 immunotherapy. © The Author(s). 2018
abstractGer	Background TGFβ signaling plays a pleotropic role in tumor biology, promoting tumor proliferation, invasion and metastasis, and escape from immune surveillance. Inhibiting TGFβ’s immune suppressive effects has become of particular interest as a way to increase the benefit of cancer immunotherapy. Here we utilized preclinical models to explore the impact of the clinical stage TGFβ pathway inhibitor, galunisertib, on anti-tumor immunity at clinically relevant doses. Results In vitro treatment with galunisertib reversed TGFβ and regulatory T cell mediated suppression of human T cell proliferation. In vivo treatment of mice with established 4T1-LP tumors resulted in strong dose-dependent anti-tumor activity with close to 100% inhibition of tumor growth and complete regressions upon cessation of treatment in 50% of animals. This effect was CD8+ T cell dependent, and led to increased T cell numbers in treated tumors. Mice with durable regressions rejected tumor rechallenge, demonstrating the establishment of immunological memory. Consequently, mice that rejected immunogenic 4T1-LP tumors were able to resist rechallenge with poorly immunogenic 4 T1 parental cells, suggesting the development of a secondary immune response via antigen spreading as a consequence of effective tumor targeting. Combination of galunisertib with PD-L1 blockade resulted in improved tumor growth inhibition and complete regressions in colon carcinoma models, demonstrating the potential synergy when cotargeting TGFβ and PD-1/PD-L1 pathways. Combination therapy was associated with enhanced anti-tumor immune related gene expression profile that was accelerated compared to anti-PD-L1 monotherapy. Conclusions Together these data highlight the ability of galunisertib to modulate T cell immunity and the therapeutic potential of combining galunisertib with current PD-1/L1 immunotherapy. © The Author(s). 2018
abstract_unstemmed	Background TGFβ signaling plays a pleotropic role in tumor biology, promoting tumor proliferation, invasion and metastasis, and escape from immune surveillance. Inhibiting TGFβ’s immune suppressive effects has become of particular interest as a way to increase the benefit of cancer immunotherapy. Here we utilized preclinical models to explore the impact of the clinical stage TGFβ pathway inhibitor, galunisertib, on anti-tumor immunity at clinically relevant doses. Results In vitro treatment with galunisertib reversed TGFβ and regulatory T cell mediated suppression of human T cell proliferation. In vivo treatment of mice with established 4T1-LP tumors resulted in strong dose-dependent anti-tumor activity with close to 100% inhibition of tumor growth and complete regressions upon cessation of treatment in 50% of animals. This effect was CD8+ T cell dependent, and led to increased T cell numbers in treated tumors. Mice with durable regressions rejected tumor rechallenge, demonstrating the establishment of immunological memory. Consequently, mice that rejected immunogenic 4T1-LP tumors were able to resist rechallenge with poorly immunogenic 4 T1 parental cells, suggesting the development of a secondary immune response via antigen spreading as a consequence of effective tumor targeting. Combination of galunisertib with PD-L1 blockade resulted in improved tumor growth inhibition and complete regressions in colon carcinoma models, demonstrating the potential synergy when cotargeting TGFβ and PD-1/PD-L1 pathways. Combination therapy was associated with enhanced anti-tumor immune related gene expression profile that was accelerated compared to anti-PD-L1 monotherapy. Conclusions Together these data highlight the ability of galunisertib to modulate T cell immunity and the therapeutic potential of combining galunisertib with current PD-1/L1 immunotherapy. © The Author(s). 2018
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title_short	Targeting the TGFβ pathway with galunisertib, a TGFβRI small molecule inhibitor, promotes anti-tumor immunity leading to durable, complete responses, as monotherapy and in combination with checkpoint blockade
url	https://dx.doi.org/10.1186/s40425-018-0356-4
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author2	Schaer, David A. Li, Yanxia Castaneda, Stephen P. Murphy, Mary Y. Xu, Xiaohong Inigo, Ivan Dobkin, Julie Manro, Jason R. Iversen, Philip W. Surguladze, David Hall, Gerald E. Novosiadly, Ruslan D. Benhadji, Karim A. Plowman, Gregory D. Kalos, Michael Driscoll, Kyla E.
author2Str	Schaer, David A. Li, Yanxia Castaneda, Stephen P. Murphy, Mary Y. Xu, Xiaohong Inigo, Ivan Dobkin, Julie Manro, Jason R. Iversen, Philip W. Surguladze, David Hall, Gerald E. Novosiadly, Ruslan D. Benhadji, Karim A. Plowman, Gregory D. Kalos, Michael Driscoll, Kyla E.
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