Peripheral blood immune correlates associated with TGF-β inhibition (galunisertib) and stereotactic body radiotherapy (SBRT) in patients with advanced hepatocellular carcinoma (HCC)

Autor: Andrzej P. Wojcieszynski, Thomas Benjamin Karasic, Lisa DiCicco, Edgar Ben-Josef, Robert H. Vonderheide, Emma E. Furth, Luis Garcia-Marcano, Kim A. Reiss, Nevena Damjanov, Michael A. Giannone, Gregory L. Beatty, Elizabeth Prechtel Dunphy, Max M. Wattenberg
Rok vydání: 2020
Předmět:
Zdroj: Journal of Clinical Oncology. 38:4575-4575
ISSN: 1527-7755
0732-183X
DOI: 10.1200/jco.2020.38.15_suppl.4575
Popis: 4575 Background: TGF-β is a pleiotropic cytokine with immunosuppressive activity. In mouse models, blockade of TGF-β signaling enhances the activity of radiation and invokes T cell dependent anti-tumor immunity. We previously reported preliminary safety and efficacy results from a pilot study combining galunisertib (LY2157299), an oral TGF-β inhibitor, with SBRT for the treatment of patients with advanced HCC. Here, we investigate immunological mechanisms and potential biomarkers associated with therapeutic activity. Methods: Patients with advanced HCC who had progressed on or refused sorafenib were treated with galunisertib (150 mg PO BID) on days 1-14 of each 28-day cycle. SBRT (18 Gy) was delivered in a single dose between days 15-28 of cycle 1. Blood was collected at baseline, following two weeks of galunisertib and following SBRT for high-dimensional analysis using a 37-marker CyTOF panel. Patients were dichotomized based on best response as either progressor (PD) or non-progressor (PR+SD). The frequency of immune subsets was compared between groups. Results: Fifteen patients were enrolled and treated. One patient was not evaluable. The most common adverse event was grade 1 or 2 fatigue in 53% of patients. The only possibly-related grade 3 event was achalasia in one patient which coincided with disease progression. Two patients achieved a PR and six patients had SD (DCR 57%) with a median progression-free survival of 3.7 months and a median overall survival of 9.0 months. For most patients, regardless of outcome, galunisertib treatment was associated with a decrease in activated Ki67+ Treg cells. However, pre-treatment immune composition within the blood of progressors and non-progressors was distinct. At baseline, progressors had an increased frequency of naive-like CD8+ T cells, whereas non-progressors had an increased frequency of non-classical monocytes. After combination therapy, only non-progressors showed a significant increase in CD8+PD1+TIGIT+ T cells. Conclusions: Galunisertib combined with SBRT was well-tolerated with modest efficacy. Immune profiling of the blood revealed distinct pre- and post-treatment signatures that differentiated patients with progression versus non-progression. These findings show that the combination of anti-TGF-β therapy with radiation can mediate disease control and identify potential correlates of efficacy. Clinical trial information: NCT02906397 .
Databáze: OpenAIRE
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