Tivozanib mediated inhibition of c-Kit/SCF signaling on Tregs and MDSCs and reversal of tumor induced immune suppression correlates with survival of HCC patients

Abstract

The immune modulatory effect of tivozanib, a tyrosine kinase inhibitor, and the underlying immune mechanisms impacting survival of HCC patients have not been investigated. Pre-clinical studies have shown that tivozanib reduces Tregs and MDSCs accumulation through inhibition of c-Kit/SCF axis. We rationalized that c-Kit/SCF axis antagonism by tivozanib may reverse tumor-induced immune suppression in HCC patients. The frequency of circulating Tregs, MDSCs, CTLA-4 + Tregs, PD-1 + T cells, c-Kit + pERK-2 + Tregs, and c-Kit + pERK-2 + MDSCs were quantified in HCC patients at baseline and two time points during tivozanib treatment. We report for the first time that reduction in Tregs after tivozanib treatment and increased levels of baseline CD4 + PD-1 + T cells correlated with significant improvement in overall survival (OS) of the patients and these signatures may be potential biomarkers of prognostic significance. This immune modulation resulted from tivozanib-mediated blockade of c-Kit/SCF signaling, impacting ERK2 phosphorylation on Tregs and MDSCs. Low pre-treatment CD4 + T cells: Treg ratio and reduction in the frequencies of Foxp3 + c-Kit + pERK + Tregs after tivozanib treatment correlated significantly with progression free survival. In a comparative analysis of tivozanib vs sorafenib treatment in HCC patients, we demonstrate that decrease in the baseline numbers or frequencies of Foxp3 + Tregs, MDSCs and exhausted T cells was significantly greater following tivozanib treatment. Additionally, greater increase in CD4 + T cell: Treg ratio after tivozanib treatment was associated with significant improvement in OS compared to sorafenib treatment, highlighting the greater efficacy of tivozanib. These insights may help identify patients who likely would benefit from c-Kit/SCF antagonism and inform efforts to improve the efficacy of tivozanib in combination with immunotherapy.

Blood-based protein profiling identifies serum protein c-KIT as a novel biomarker for hypertrophic cardiomyopathy

“…c-KIT mutations are associated with gastrointestinal, dermatological and hematological tumors [17][18][19][20][21] and c-KIT acts as a biomarker in different cancer types 22,23 . c-KIT expression has also been described in the detection and assessment of the prognosis of patients with tumors 24,25 . Recently the role of c-KIT in the development of bleomycin-induced pulmonary fibrosis was described by Ding et al 26 .…”

Mitochondrial-Related Transcriptome Feature Correlates with Prognosis, Vascular Invasion, Tumor Microenvironment, and Treatment Response in Hepatocellular Carcinoma

“…These tumor-infiltrating lymphocytes (TILs) were suggested to be related to the response of immune checkpoints such as PD-1 and PD-L1 [ 25 , 52 ], so that the efficacy of PD-1/PD-L1 inhibitors may be differed between high- and low-risk patients. Meanwhile, in patients from the high-risk group there was a significantly higher abundance of Tregs indicating the suppressive immunotherapy in HCC as reported before [ 53 ], while tivozanib [ 54 ] and cystathionine β -synthase [ 55 ] could decrease Tregs infiltration. Therefore, the combined treatment of immune checkpoint inhibitors, such as PD-1/PD-L1 inhibitors, with the antioxidant drugs and tivozanib or cystathionine β -synthase was highly recommended for the advanced HCC patients with high prognosis score.…”

Safety and Efficacy of Tivozanib in First-Line mRCC: A Multicenter Compassionate-Use Study (Meet-Uro 16)

“…Moreover, a very recent trial explored the association of tivozanib (1.5 mg daily for 3 weeks followed by 1-week rest) with nivolumab in 25 mRCC patients (52% pretreated) and reported a promising RR of 56% (including 1 complete response) and a PFS of 18.9 months [32]. Further clinical development of the association of tivozanib with checkpoint inhibitors is therefore warranted in view of the improved tolerability of this TKI and of its immune modulatory properties [5].…”

“…Pharmacokinetic studies showed a half-life slightly above 100 h, thus allowing for once-daily administration. Preclinical studies have reported that tivozanib may also have immune modulatory activities by reducing regulatory T cells and myeloid-derived suppressor cell accumulation, and their potential correlation with activity of this drug has recently been reported in a small cohort of patients with hepatocellular carcinoma [5].…”