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

Abstract

BackgroundTGFβ 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.ResultsIn 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.ConclusionsTogether 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.

TGFβ Blockade Augments PD-1 Inhibition to Promote T-Cell–Mediated Regression of Pancreatic Cancer

“…In addition, concomitant TGFb/PD-L1 pathway inhibition greatly enhanced T-cell responses in esophageal squamous cell carcinoma (21), and blockade of greatly sensitized genetically reconstituted models of colon cancer metastasis (22). Further, TGFb pathway inhibitors enhanced responsiveness to PD-1/PD-L1-neutralizing antibodies in mice bearing poorly immunogenic 4T1-LP breast tumors (23).…”

Phase 2 study of pembrolizumab and circulating biomarkers to predict anticancer response in advanced, unresectable hepatocellular carcinoma

“…3B). 20 Murine colon carcinoma and breast cancer models further illustrated that M7824 attenuates tumor burden and enhances OS compared with TGF-β blockade alone, as evidenced by elevated CD8-positive T-cell and NK cell activation. This result supports a study illustrating that TGF-β signaling diminishes tumor response to PD-1/PD-L1 blockade by excluding CD8-positive effector T cells from the tumor parenchyma.…”

“…Although these Cancer October 15, 2019 clinical trials still are ongoing and treatment outcome remains unclear, preclinical studies have demonstrated that galunisertib can increase anti-PD-L1 monotherapyelicited intratumor immune-associated gene expression. 20 Murine colon carcinoma and breast cancer models further illustrated that M7824 attenuates tumor burden and enhances OS compared with TGF-β blockade alone, as evidenced by elevated CD8-positive T-cell and NK cell activation. 21 In the current study, we did not observe any obvious correlation between PD-L1-positive tumors and response to PD-1/PD-L1 blockade, 4,13 yet early results have suggested that PD-L1 expression in immune and tumor cells was associated with response to pembrolizumab in a subset of patients with HCC.…”

Utilizing Experimental Mouse Model to Identify Effectors of Hepatocellular Carcinoma Induced by HBx Antigen

“…It illustrates an unpredicted immune regulatory mechanism that inhibits the development of antitumor immunity and may diminish the effect of immunotherapy [47]. In agreement with the idea of microenvironment, targeting the TGF-β pathway with a TGFβRI small molecule inhibitor (galunisertib) has been proven to support anti-tumor immunity in a solid tumor study [48]. The treatment with galunisertib showed strong dose-dependence with anti-tumor activities where T cell proliferation mediated by TGF-β was suppressed.…”