Abstract
AbstractBackground & AimsSystemic therapies for hepatocellular carcinoma (HCC) treatment have limited efficacy and poor safety. Dipeptidyl peptidase‐4 inhibitors were initially developed and approved as treatment for type 2 diabetes, yet oral administration of sitagliptin has recently been shown to improve naturally occurring tumour immunity in animal models of HCC.MethodsWe conducted a phase Ib clinical trial to evaluate the impact of a pre‐operative 3‐week DPP4 inhibitor (sitagliptin) treatment in HCC patients undergoing liver resection. The primary objective was to evaluate the safety of a sitagliptin treatment in each of the three groups of patients, according to an escalating dosage of sitagliptin (100, 200 and 600 mg/d). Secondary objectives included the assessment of DPP4 activity, cytokine expression in plasma samples and circulating immune populations.ResultsFourteen patients were included and analysed. In all three dose groups, no severe adverse event related to sitagliptin was reported. A significant inhibition of DPP4 activity was observed upon sitagliptin treatment, which prevented the N‐terminal truncation of CXCL10, leading to a mobilization of circulating CD8+ T cells and eosinophils. Immunochemistry analysis showed a lymphoid infiltration in all tumour samples with the presence of a population of CXCR3+ T cells in all but one of the tumours. Positivity for CXCL10 (IP10) and CCR3 in tumour and/or stroma cells was found in all resection pieces.ConclusionIn summary, sitagliptin can be used safely in patients with chronic liver disease and HCC, and could be tested in phase 2 trial, as an adjuvant in combination with others drugs, for the treatment of HCC patients.
Highlights
Hepatocellular carcinoma (HCC) is the fifth most common cancer, and third most common cause of cancer-related mortality worldwide.[1]
We reported that DPP4 inhibition through oral administration of sitagliptin improved naturally occurring tumour immunity in animal models of melanoma, colorectal carcinoma, as well as hepatocellular carcinoma (HCC)
While this improved tumour control was due to increased T cell recruitment through perservation of functional CXCL10 in melanoma and colorectal carcinoma,[8] DPP4 inhibition efficacy in HCC models was driven by and increased eosinophil migration into tumours, mediated by CCL11 and tumour expression of IL-33.9
Summary
• Sitagliptin as a neoadjuvant treatment in hepatocellular carcinoma. • Sitagliptin as an immunotherapy in hepatocellular carcinoma. • Safety of Sitagliptin in chronic liver disease patients with hepatocellular carcinoma. • Sitagliptin improves leucocyte trafficking in hepatocellular carcinoma
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