PT - JOURNAL ARTICLE AU - Rikke B. Holmgaard AU - David A. Schaer AU - Yanxia Li AU - Stephen P. Castaneda AU - Mary Y. Murphy AU - Xiaohong Xu AU - Ivan Inigo AU - Julie Dobkin AU - Jason R. Manro AU - Philip W. Iversen AU - David Surguladze AU - Gerald E. Hall AU - Ruslan D. Novosiadly AU - Karim A. Benhadji AU - Gregory D. Plowman AU - Michael Kalos AU - Kyla E. Driscoll TI - 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 AID - 10.1186/s40425-018-0356-4 DP - 2018 Dec 01 TA - Journal for ImmunoTherapy of Cancer PG - 47 VI - 6 IP - 1 4099 - http://jitc.bmj.com/content/6/1/47.short 4100 - http://jitc.bmj.com/content/6/1/47.full SO - J Immunother Cancer2018 Dec 01; 6 AB - 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.Rikke B. Holmgaard and David Schaer contributed equally to this work.