Safety of sitagliptin in treatment of hepatocellular carcinoma in chronic liver disease patients. Issue 3 (28th August 2021)

• Record Type: Journal Article
• Authors: Hollande, Clémence; Boussier, Jeremy; Mottez, Estelle; Bondet, Vincent; Buivan, Tan Phuc; Charbit, Bruno; Llibre, Alba; Charlotte, Frédéric; Savier, Eric; Scatton, Olivier; Duffy, Darragh; Albert, Matthew; Mallet, Vincent; Pol, Stanislas
• Is Part Of: Liver Cancer International. Volume 2:Issue 3(2021)
• Page Start: 73
• Page End: 81
• Publication Date: 2021-08-28
• Subjects: dipeptidyl peptidase 4 -- hepatocellular carcinoma -- leucocyte trafficking -- neoadjuvant therapy -- sitagliptin; Liver -- Cancer -- Periodicals; 616.99436
• DOI: 10.1002/lci2.36
• Languages: English
• ISSNs: 2642-3561

Abstract

Abstract: Background & Aims: Systemic 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. Methods: We 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. Results: Fourteen 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. Conclusion: In 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.