Targeting Tumor Angiogenesis with the Selective VEGFR-3 Inhibitor EVT801 in Combination with Cancer Immunotherapy.

The receptor tyrosine kinase VEGFR-3 plays a crucial role in cancer-induced angiogenesis and lymphangiogenesis, promoting tumor development and metastasis. Here, we report the novel VEGFR-3 inhibitor EVT801 that presents a more selective and less toxic profile than two major inhibitors of VEGFRs (i.e., sorafenib and pazopanib). As monotherapy, EVT801 showed a potent antitumor effect in VEGFR-3-positive tumors, and in tumors with VEGFR-3-positive microenvironments. EVT801 suppressed VEGF-C-induced human endothelial cell proliferation in vitro and tumor (lymph)angiogenesis in different tumor mouse models. In addition to reduced tumor growth, EVT801 decreased tumor hypoxia, favored sustained tumor blood vessel homogenization (i.e., leaving fewer and overall larger vessels), and reduced important immunosuppressive cytokines (CCL4, CCL5) and myeloid-derived suppressor cells (MDSC) in circulation. Furthermore, in carcinoma mouse models, the combination of EVT801 with immune checkpoint therapy (ICT) yielded superior outcomes to either single treatment. Moreover, tumor growth inhibition was inversely correlated with levels of CCL4, CCL5, and MDSCs after treatment with EVT801, either alone or combined with ICT. Taken together, EVT801 represents a promising anti(lymph)angiogenic drug for improving ICT response rates in patients with VEGFR-3 positive tumors. Significance: The VEGFR-3 inhibitor EVT801 demonstrates superior selectivity and toxicity profile than other VEGFR-3 tyrosine kinase inhibitors. EVT801 showed potent antitumor effects in VEGFR-3-positive tumors, and tumors with VEGFR-3-positive microenvironments through blood vessel homogenization, and reduction of tumor hypoxia and limited immunosuppression. EVT801 increases immune checkpoint inhibitors' antitumor effects.

Characterization of overlap syndrome between primary biliary cirrhosis and autoimmune hepatitis according to antimitochondrial antibodies status.

AIMS: Codification of variant forms between Primary Biliary Cirrhosis (PBC) and Autoimmune Hepatitis (AIH) has not been definitively standardized. The aim of this study was to compare among 102 consecutive patients, 2 subsets of overlap syndrome (OS, N=21) with and without antimitochondrial antibody (AMA) to two groups of patients with typical PBC (N=43) or AIH (N=38). METHODS: OS was defined by the presence in the same patient of at least 2 of 3 accepted criteria of PBC and AIH. Twelve patients with OS were AMA negative and 9 were AMA positive. RESULTS: A lower level of alanine transaminase (139+/-48 vs 269+/-154 IU/L, P<0.05) and a trend towards a higher level of alkaline phosphatase or gamma-glutamyl transpeptidase was observed in OS without AMA than in OS with AMA (693+/-200 vs 544+/-124 IU/L; 370+/-66 vs 241+/-77 IU/L, respectively). All AMA-negative patients with OS had antinuclear and/or anti-smooth muscle antibodies. OS without AMA differed from those with AMA in that they had more severe bile duct damage including destructive cholangitis (P<0.05), ductopenia (P<0.05), ductular hyperplasia (P<0.05) and a higher METAVIR fibrosis score (2.5+/-0.3 vs 1.3+/-0.3, P<0.05). The response to therapy was not different between PBC, AIH and OS. CONCLUSIONS: According to the presence of AMA, 2 homogeneous subgroups of patients with overlap syndrome between PBC and AIH may be identified. AMA status affects clinical presentation and liver disease severity of OS.

Long-term impact of renal transplantation on liver fibrosis during hepatitis C virus infection.

BACKGROUND & AIMS: During hepatitis C virus (HCV) infection, liver fibrosis progression after renal transplantation remains controversial. The aim of this cohort study with controls was to compare liver histopathologic features during HCV infection between renal transplant recipients and matched groups of hemodialyzed patients or controls without renal disease and untreated for HCV. METHODS: Each renal transplant recipient (group 1, n = 30) was matched at first liver biopsy (LB) using the main factors known to influence progression of fibrosis with one HCV hemodialyzed patient (group 2, n = 30) and one HCV-infected patient (nonhemodialyzed, nontransplanted; group 3, n = 30). Patients from group 1 were also matched with those of group 3 on the time between 2 consecutive LBs performed 37 months apart. LBs were evaluated according to the Knodell index, METAVIR score, and rate of fibrosis progression per year (fibrosis unit). RESULTS: The rate of fibrosis progression per year between the first and second LBs was significantly lower (P = 0.03) in group 1 (0.067; 95% confidence interval: -0.05, 0.18) than group 3 (0.20; 95% confidence interval: 0.13, 0.26). At the second LB, the Knodell index and activity or fibrosis in METAVIR were lower in group 1 than group 3 (4.2 +/- 0.4 vs. 7.5 +/- 0.6, 0.5 +/- 0.1 vs. 1.3 +/- 0.2, and 1.4 +/- 0.2 vs. 2.3 +/- 0.2 respectively, P < 0.01). CONCLUSIONS: Our study suggests that liver fibrosis progression is low in most HCV-infected renal transplant recipients with moderate liver disease at baseline.