Abstract 1415: Targeting the TGFβ pathway with galunisertib, a small molecule inhibitor of TGFβRI, promotes anti-tumor immunity leading to durable, complete responses, as monotherapy and in combination with checkpoint inhibition
Authors: Schaer David , Driscoll Kyla 
Published: July 2016

Abstract
TGFβ signaling is known to play a central role in tumor biology, via inducing and/or enhancing tumor cell growth and differentiation, modulating the extracellular matrix in the stroma, inducing epithelial to mesenchymal transition, modulating angiogenesis, and inhibiting immune surveillance and anti-tumor immunity. Galunisertib is a pharmacological inhibitor of the TGFβ pathway which acts by inhibiting signaling though TGFβRI. Galunisertib is currently being evaluated clinically in several Phase I and II studies; as a monotherapy, galunisertib has shown antitumor activity against a variety of tumors, including durable and long-term responses in patients with glioma.
To explore the impact of Galunisertib monotherapy on anti-tumor T cell immunity, we utilized murine tumor models. Treatment of mice with 4T1-LP (poorly immunogenic 4T1 breast tumor engineered to express luciferase) implanted in the mammary fat pad resulted in strong dose-dependent anti-tumor activity with nearly 100% inhibition of tumor growth across doses during the dosing period, with complete tumor rejection upon cessation of treatment in ∼50% of animals at the highest dose tested; depletion studies demonstrated that rejection of 4T1-LP was dependent on the presence of CD8+ T cells. Rechallenge of treated, tumor free mice resulted in complete rejection of 4T1-LP tumor cells but no rejection of EMT6-LM2 tumor cells, demonstrating the establishment of a durable response and immunological memory. Treatment of mice bearing parental 4T1 tumors in the mammary fat pad resulted in no significant inhibition of tumor growth, indicating that the presence of a foreign antigen (i.e. LP), potentially enhanced the ability to reject the 4T1-LP derivative. Animals that rejected the immunogenic 4T1-LP cells were able to also reject 4T1 parental cells upon rechallenge, suggesting the development of a secondary immune response via antigen spreading as a consequence of effective tumor targeting. In the CT26 murine colon carcinoma model, treatment with galunisertib or anti-PD-L1 as monotherapies resulted in tumor growth inhibition compared to control of 75% and 86%, respectively (T/C values of 25% and 14%); complete responders were observed in about 20% of treated animals in both monotherapy groups. Combination of galunisertib with anti-PD-L1 resulted in an enhanced tumor growth inhibition of 98% (T/C value of ∼2%), and a complete response rate of ∼50%, suggesting at least additive activity with potential for synergy when targeting the TGFβ and PD-1 pathways. Taken together, these data demonstrate the potential for galunisertib treatment to enhance the development of anti- tumor T cell immunity, which can be enhanced by combinations with immune check point inhibitors.
Citation Format: David Schaer, Kyla Driscoll. Targeting the TGFβ pathway with galunisertib, a small molecule inhibitor of TGFβRI, promotes anti-tumor immunity leading to durable, complete responses, as monotherapy and in combination with checkpoint inhibition. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1415.