Immune Therapy for Liver Cancers

Abstract

Hepatocellular carcinoma (HCC) and biliary tract cancers (BTC) display a poor prognosis with 5-year overall survival rates around 15%, all stages taken together. These primary liver malignancies are often diagnosed at advanced stages where therapeutic options are limited. Recently, immune therapy has opened new opportunities in oncology. Based on their high programmed death-ligand 1 expression and tumor-infiltrating lymphocytes, HCC and BTC are theoretically good candidates for immune checkpoint blockade. However, clinical activity of single agent immunotherapy appears limited to a subset of patients, which is still ill-defined, and combinations are under investigation. In this review, we provide an overview of (i) the biological rationale for immunotherapies in HCC and BTC, (ii) the current state of their clinical development, and (iii) the predictive value of immune signatures for both clinical outcome and response to these therapies.

Anticancer Activity of Rosmarinus officinalis L.: Mechanisms of Action and Therapeutic Potentials

“…Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer, and the third leading cause of cancer death [57].…”

Role of Immune Checkpoint Inhibitors in Gastrointestinal Malignancies

“…Some ongoing Phase III ICIs combination studies include: Nivolumab plus ipilimumab in advanced HCC as first line therapy (NCT03510871, NCT03222076, NCT03203304, NCT01658878, NCT04039607) and durvalumab plus tremelimumab in advanced HCC as second line therapy (NCT03298451) [54]. Phase III studies involving ICI and angiogenesis inhibitors include: nivolumab plus sorafenib in advanced HCC as first line therapy (NCT02576509, NCT01658878, NCT03439891), pembrolizumab plus lenvatinib in patients with advanced HCC as first line therapy (NCT03713593), atezolizumab plus cabozantinib in advanced HCC as first line therapy (NCT03755791), atezolizumab plus bevacizumab in advanced HCC as first line therapy (NCT03434379), durvalumab plus bevacizumab in localized and locally advanced HCC (NCT03847428, NCT03778957), camrelizumab plus apatinib in advanced HCC as first line therapy (NCT02942329, NCT03764293), tislelizumab plus sorafenib for advanced HCC as first line therapy (NCT03412773) and sintilimab plus IBI305 in advanced HCC as first line therapy (NCT03794440) [54]. All studies involving ICIs plus locoregional therapies (radiofrequency ablation, radiotherapy or intra-arterial treatments), ICIs plus chemotherapy, ICIs plus TGF-beta inhibitors, ICIs plus indoleamine dioxygenase inhibitors and others are all in phase I/II stages [54].…”

“…There are ongoing phase II trials with first line combination nivolumab plus ipilimumab in advanced cholangiocarcinoma (NCT03101566, NCT02834013), second line pembrolizumab monotherapy in advanced cholangiocarcinoma (NCT03110328, NCT02628067), second line nivolumab in advanced cholangiocarcinoma (NCT02829918), first line durvalumab and tremelimumab with chemotherapy in advanced cholangiocarcinoma (NCT03473574, NCT03046862, NCT03704480), first line toripalimab with chemotherapy in advanced cholangiocarcinoma (NCT03796429, NCT03982680, NCT04027764) [54]. There are ongoing phase III trials of first line durvalumab with chemotherapy for advanced cholangiocarcinoma (NCT03875235) and first line pembrolizumab with chemotherapy in advanced cholangiocarcinoma (NCT03260712, NCT03111732, NCT04003636) [54]. There is a huge unmet need to have efficacious drugs for this tumor type in advanced setting, considering the overall survival is dismal in this disease.…”

Mitochondrial uncoupling and the disruption of the metabolic network in hepatocellular carcinoma

“…In recent years, sorafenib, a known multi-kinase inhibitor, became the first-line treatment for advanced-stage HCC, but unfortunately provided limited improvement in patient survival [2]. Although other kinase and immune checkpoint inhibitors are now considered second-line options, the data supporting improved outcomes relative to sorafinib is not yet compelling [3,4].…”

“…Because to the lack of treatment options in advanced cases, our group and others have developed strategies using small-molecules targeting different pathways with or without immunotherapy for late stages in pre-clinical or clinical studies [3][4][5][6][7][8][9][10][11]. The Wnt/βcatenin pathway is critical for HCC cell proliferation, progression and stemness, and this pathway is aberrant in 30-50% of the HCC tumors [12][13][14][15][16].…”