RT Journal Article
SR Electronic
T1 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
JF Journal for ImmunoTherapy of Cancer
JO J Immunother Cancer
FD BMJ Publishing Group Ltd
SP 47
DO 10.1186/s40425-018-0356-4
VO 6
IS 1
A1 Rikke B. Holmgaard
A1 David A. Schaer
A1 Yanxia Li
A1 Stephen P. Castaneda
A1 Mary Y. Murphy
A1 Xiaohong Xu
A1 Ivan Inigo
A1 Julie Dobkin
A1 Jason R. Manro
A1 Philip W. Iversen
A1 David Surguladze
A1 Gerald E. Hall
A1 Ruslan D. Novosiadly
A1 Karim A. Benhadji
A1 Gregory D. Plowman
A1 Michael Kalos
A1 Kyla E. Driscoll
YR 2018
UL http://jitc.bmj.com/content/6/1/47.abstract
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.