Galunisertib, a small molecule inhibitor of TGFβ receptor I kinase that is currently in clinical trials, reduced tumor growth and induced complete regression in some mice with immunogenic tumors in a CD8+ T cell-dependent manner. Galunisertib blocked Treg-mediated suppression and led to formation of immunological memory in a manner that indicated epitope spreading. Combination of galunisertib and anti-PD-L1 enhanced tumor regression compared with either monotherapy, and comprehensive gene expression analysis indicated that combination therapy accelerated T cell activation.
BACKGROUND: TGFbeta signaling plays a pleotropic role in tumor biology, promoting tumor proliferation, invasion and metastasis, and escape from immune surveillance. Inhibiting TGFbeta'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 TGFbeta pathway inhibitor, galunisertib, on anti-tumor immunity at clinically relevant doses. RESULTS: In vitro treatment with galunisertib reversed TGFbeta 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 TGFbeta 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.
Author Info: (1) Eli Lilly and Company, 450 East 29th Street, New York, USA. (2) Eli Lilly and Company, 450 East 29th Street, New York, USA. (3) Eli Lilly and Company, 450 East 29th Street, New
Author Info: (1) Eli Lilly and Company, 450 East 29th Street, New York, USA. (2) Eli Lilly and Company, 450 East 29th Street, New York, USA. (3) Eli Lilly and Company, 450 East 29th Street, New York, USA. (4) Eli Lilly and Company, 450 East 29th Street, New York, USA. (5) Eli Lilly and Company, 450 East 29th Street, New York, USA. (6) Eli Lilly and Company, 450 East 29th Street, New York, USA. (7) Eli Lilly and Company, 450 East 29th Street, New York, USA. (8) Eli Lilly and Company, 450 East 29th Street, New York, USA. (9) Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46285, USA. (10) Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, 46285, USA. (11) Eli Lilly and Company, 450 East 29th Street, New York, USA. (12) Eli Lilly and Company, 450 East 29th Street, New York, USA. (13) Eli Lilly and Company, 450 East 29th Street, New York, USA. (14) Eli Lilly and Company, 450 East 29th Street, New York, USA. (15) Eli Lilly and Company, 450 East 29th Street, New York, USA. (16) Eli Lilly and Company, 450 East 29th Street, New York, USA. Janssen Pharmaceutical Companies of Johnson and Johnson, Spring House, PA, USA. (17) Eli Lilly and Company, 450 East 29th Street, New York, USA. Driscoll_kyla@lilly.com.
