Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of conditions ranging from hepatic steatosis to inflammation (nonalcoholic steatohepatitis or NASH) with or without fibrosis, in the absence of significant alcohol consumption. The presence of fibrosis in NASH patients is associated with greater liver-related morbidity and mortality; however, the molecular mechanisms underlying the development of fibrosis and cirrhosis in NAFLD patients remain poorly understood. Long non-coding RNAs (lncRNAs) are emerging as key contributors to biological processes that are underpinning the initiation and progression of NAFLD fibrosis. This review summarizes the experimental findings that have been obtained to date in animal models of liver fibrosis and NAFLD patients with fibrosis. We also discuss the potential applicability of circulating lncRNAs to serve as biomarkers for the diagnosis and prognosis of NAFLD fibrosis. A better understanding of the role played by lncRNAs in NAFLD fibrosis is critical for the identification of novel therapeutic targets for drug development and improved, noninvasive methods for disease diagnosis.

Factors governing the development of liver fibrosis in nonalcoholic steatohepatitis (NASH) are only partially understood. We recently identified adipocyte enhancer binding protein 1 ( AEBP1 ) as a member of a core set of dysregulated fibrosis-specific genes in human NASH. Here we sought to investigate the relationship between AEBP1 and hepatic fibrosis. We confirmed that hepatic AEBP1 expression is elevated in fibrosis compared to lobular inflammation, steatosis, and normal liver, and increases with worsening fibrosis in NASH patients. AEBP1 expression was upregulated 5.8-fold in activated hepatic stellate cells and downregulated during chemical and contact induction of biological quiescence. In LX-2 and HepG2 cells treated with high glucose (25 mM), AEBP1 expression increased over 7-fold compared to normal glucose conditions. In response to treatment with either fructose or palmitate, AEBP1 expression in primary human hepatocytes increased 2.4-fold or 9.6-fold, but was upregulated 55.8-fold in the presence of fructose and palmitate together. AEBP1 knockdown resulted in decreased expression of nine genes previously identified to be part of a predicted AEBP1 -associated NASH co-regulatory network and confirmed to be upregulated in fibrotic tissue. We identified binding sites for two miRNAs known to be downregulated in NASH fibrosis, miR-372-3p and miR-373-3p in the AEBP1 3’ untranslated region. Both miRNAs functionally interacted with AEBP1 to regulate its expression. These findings indicate a novel AEBP1 -mediated pathway in the pathogenesis of hepatic fibrosis in NASH.

Purpose: The First-in-Human Phase 1/2 ICONIC trial evaluated an investigational ICOS agonist, vopratelimab, alone and in combination with nivolumab in patients with advanced solid tumors. Experimental Design: In Phase 1, patients were treated with escalating doses of intravenous vopratelimab alone or with nivolumab. Primary objectives were safety, tolerability, maximum tolerated dose and recommended Phase 2 dose (RP2D). Phase 2 enriched for ICOS+ tumors; patients were treated with vopratelimab at the monotherapy RP2D alone or with nivolumab. Pharmacokinetics, pharmacodynamics and predictive biomarkers of response to vopratelimab were assessed. Results: ICONIC enrolled 201 patients. Vopratelimab alone and with nivolumab was well tolerated; Phase 1 established 0.3 mg/kg q3w as the vopratelimab RP2D. Vopratelimab resulted in modest objective response rates of 1.4% and with nivolumab of 2.3%. The prospective selection for ICOS+ tumors did not enrich for responses. A vopratelimab-specific peripheral blood pharmacodynamic biomarker, ICOS-hi CD4 T-cells, was identified in a subset of patients who demonstrated greater clinical benefit versus those with no emergence of these cells [overall survival (OS), p=0.0025]. A potential genomic predictive biomarker of ICOS-hi CD4 T-cell emergence was identified which demonstrated improvement in clinical outcomes, including OS (p=0.0062). Conclusions: Vopratelimab demonstrated a favorable safety profile alone and in combination with nivolumab. Efficacy was observed only in a subset of patients with a vopratelimab-specific pharmacodynamic biomarker. A potential predictive biomarker of response was identified, which is being prospectively evaluated in a randomized Phase 2 non-small cell lung cancer trial.

Immunotherapy checkpoint inhibitors, such as antibodies targeting PD-1 and CTLA-4, have demonstrated the potential of harnessing the immune system to treat cancer. However, despite encouraging results particularly with respect to survival, only a minority of patients benefit from these therapies. In clinical studies aimed at understanding changes in the immune system following immunotherapy treatment, ICOS (Inducible T cell CO-Stimulator) was shown to be significantly up-regulated on CD4+ T cells and this was associated with clinical activity, indicating that ICOS stimulatory activity may be beneficial in the treatment of solid tumors. In this report, we describe the generation of specific, species cross-reactive, agonist antibodies to ICOS, including the humanized clinical candidate, JTX-2011 (vopratelimab). Preclinical studies suggest that the ICOS stimulating antibodies require Fc receptor cross-linking for optimal agonistic activity. Notably, the ICOS antibodies do not exhibit superagonist properties but rather require T cell receptor (TCR)-mediated upregulation of ICOS for agonist activity. Treatment with the ICOS antibodies results in robust anti-tumor benefit and long-term protection in preclinical syngeneic mouse tumor models. Additional benefit is observed when the ICOS antibodies are administered in combination with anti-PD-1 and anti-CTLA-4 therapies. Based on the preclinical data, JTX-2011 is currently being developed in the clinical setting for the treatment of solid tumors.

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