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Targeting the TGF? pathway with galunisertib, a TGF?RI small molecule inhibitor, promotes anti-tumor immunity leading to durable, complete responses, as monotherapy and in combination with checkpoint blockade.

ABSTRACT: BACKGROUND:TGF? signaling plays a pleotropic role in tumor biology, promoting tumor proliferation, invasion and metastasis, and escape from immune surveillance. Inhibiting TGF?'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 TGF? pathway inhibitor, galunisertib, on anti-tumor immunity at clinically relevant doses. RESULTS:In vitro treatment with galunisertib reversed TGF? 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 TGF? 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.

SUBMITTER: Holmgaard RB

PROVIDER: S-EPMC5987416 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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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.

Holmgaard Rikke B RB Schaer David A DA Li Yanxia Y Castaneda Stephen P SP Murphy Mary Y MY Xu Xiaohong X Inigo Ivan I Dobkin Julie J Manro Jason R JR Iversen Philip W PW Surguladze David D Hall Gerald E GE Novosiadly Ruslan D RD Benhadji Karim A KA Plowman Gregory D GD Kalos Michael M Driscoll Kyla E KE

Journal for immunotherapy of cancer 20180604 1

<h4>Background</h4>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.<h4>Results</h4>In vitro ...[more]

PMID: 29866156

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Project description:BackgroundThe combination of galunisertib, a transforming growth factor (TGF)-? receptor (R)1 kinase inhibitor, and lomustine was found to have antitumor activity in murine models of glioblastoma.MethodsGalunisertib (300 mg/day) was given orally 14 days on/14 days off (intermittent dosing). Lomustine was given as approved. Patients were randomized in a 2:1:1 ratio to galunisertib + lomustine, galunisertib monotherapy, or placebo + lomustine. The primary objective was overall survival (OS); secondary objectives were safety, pharmacokinetics (PKs), and antitumor activity.ResultsOne hundred fifty-eight patients were randomized: galunisertib + lomustine (N = 79), galunisertib (N = 39), and placebo + lomustine (N = 40). Baseline characteristics were: male (64.6%), white (75.3%), median age 58 years, ECOG performance status (PS) 1 (63.3%), and primary glioblastoma (93.7%). The PKs of galunisertib were not altered with lomustine, and galunisertib had a median half-life of ?8 hours. Median OS in months (95% credible interval [CrI]) for galunisertib + lomustine was 6.7 (range: 5.3-8.5), 8.0 (range: 5.7-11.7) for galunisertib alone, and 7.5 (range: 5.6-10.3) for placebo + lomustine. There was no difference in OS for patients treated with galunisertib + lomustine compared with placebo + lomustine [P (HR < 1) = 26%]. Median progression-free survival of ?2 months was observed in all 3 arms. Among 8 patients with IDH1 mutation, 7 patients were treated with galunisertib (monotherapy or with lomustine); OS ranged from 4 to 17 months. Patients treated with galunisertib alone had fewer drug-related grade 3/4 adverse events (n = 34) compared with lomustine-treated patients (10% vs 26%). Baseline PS, post-discontinuation of bevacizumab, tumor size, and baseline levels of MDC/CCL22 were correlated with OS.ConclusionsGalunisertib + lomustine failed to demonstrate improved OS relative to placebo + lomustine. Efficacy outcomes were similar in all 3 arms.Clinical trial registrationNCT01582269, ClinicalTrials.gov.

Project description:(1) Background: The immune checkpoint blockade (ICB) has shown promising efficacy in non-small-cell lung cancer (NSCLC) patients with significant clinical benefits and durable responses, but the overall response rate to ICBs is only 20%. The lack of responsiveness to ICBs is currently a central problem in cancer immunotherapy. (2) Methods: Four public cohorts comprising 2986 patients with NSCLC were included in the study. We screened 158 patients with NSCLC with no durable clinical benefit (NDB) to ICBs in the Rizvi cohort and identified NDB-related gene mutations in these patients using univariate and multivariate Cox regression analyses. Programmed death-ligand 1 (PD-L1) expression, tumor mutation burden (TMB), neoantigen load, tumor-infiltrating lymphocytes, and immune-related gene expression were analyzed for identifying gene mutations. A comprehensive predictive classifier model was also built to evaluate the efficacy of ICB therapy. (3) Results: Mutations in FAT1 and KEAP1 were found to correlate with NDB in patients with NSCLC to ICBs; however, the analysis suggested that only mutation in FAT1 was valuable in predicting the efficacy of ICB therapy, and that mutation in KEAP1 acted as a prognostic but not a predictive biomarker for NSCLC. Mutations in FAT1 were associated with a higher TMB and lower multiple lymphocyte infiltration, including CD8 (T-Cell Surface Glycoprotein CD8)+ T cells. We established a prognostic model according to PD-L1 expression, TMB, smoking status, treatment regimen, treatment type, and FAT1 mutation, which indicated good accuracy by receiver operating characteristic (ROC) analysis (area under the curve (AUC) for 6-months survival: 0.763; AUC for 12-months survival: 0.871). (4) Conclusions: Mutation in FAT1 may be a predictive biomarker in patients with NSCLC who exhibit NDB to ICBs. We proposed an FAT1 mutation-based model for screening more suitable NSCLC patients to receive ICBs that may contribute to individualized immunotherapy.

Project description:BackgroundImmune checkpoint blocker (ICB) has shown significant clinical activity in melanoma. However, there are no clinically approved biomarkers to aid patient selection. We aimed to identify patients with advanced or metastatic melanoma who are likely to benefit from ICB monotherapy using easily accessible clinical indicators.Materials and methodsWe retrospectively reviewed the records of 134 patients with advanced or metastatic melanoma who received ICB monotherapy between 2014 and 2018. Prognostic factors of overall survival (OS) and progression-free survival (PFS) were determined using Cox regression analysis.ResultsDuring the median follow-up of 13.7 months, the median OS and PFS were 18.4 and 3.4 months, respectively. Visceral/central nervous system (CNS) metastasis (OS: adjusted hazards ratio [HR], 1.82; p=.014; PFS: HR, 1.59; p=.024), lymphopenia (<1000 cells/µL) within 3 months (OS: HR, 1.89, p=.006; PFS: HR, 1.70; p=.010), and elevated baseline lactate dehydrogenase (LDH) level (OS: HR, 2.61; p<.001; PFS: HR, 2.66; p<.001) were independent prognostic factors for both poor OS and PFS. Development of immune-related adverse events (irAE; e.g., hypothyroidism or vitiligo) within 6 months showed a trend toward better OS in multivariable analysis (HR, 0.37; p=.058). Patients with normal LDH levels and no visceral/CNS metastasis had a substantially better OS than the others (median, 40.4 vs. 13.6 months; p<.001). Among others, patients who developed irAE within 6 months achieved long-term OS (median, 43.6 vs. 13.1 months; p=.008). A decision tree was suggested using four risk factors, and the risk stratification provided significant distinction between the survival curves.ConclusionThe four easily accessible clinical indicators associated with better treatment outcomes after ICB monotherapy in patients with advanced or metastatic melanoma were LDH level, the extent of disease, lymphopenia, and irAE. The combined use of these indicators can be clinically useful in improving risk stratification of patients treated with ICB monotherapy.

Dataset Information

Targeting the TGF? pathway with galunisertib, a TGF?RI small molecule inhibitor, promotes anti-tumor immunity leading to durable, complete responses, as monotherapy and in combination with checkpoint blockade.

Publications

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.

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