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


ABSTRACT: BACKGROUND:TGF? signaling plays a pleotropic role in tumor biology, promoting tumor proliferation, invasion and metastasis, and escape from immune surveillance. Inhibiting TGF?'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 TGF? pathway inhibitor, galunisertib, on anti-tumor immunity at clinically relevant doses. RESULTS:In vitro treatment with galunisertib reversed TGF? 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 TGF? 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.

SUBMITTER: Holmgaard RB 

PROVIDER: S-EPMC5987416 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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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.

Holmgaard Rikke B RB   Schaer David A DA   Li Yanxia Y   Castaneda Stephen P SP   Murphy Mary Y MY   Xu Xiaohong X   Inigo Ivan I   Dobkin Julie J   Manro Jason R JR   Iversen Philip W PW   Surguladze David D   Hall Gerald E GE   Novosiadly Ruslan D RD   Benhadji Karim A KA   Plowman Gregory D GD   Kalos Michael M   Driscoll Kyla E KE  

Journal for immunotherapy of cancer 20180604 1


<h4>Background</h4>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.<h4>Results</h4>In vitro  ...[more]

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