Specific CD8(+) T cell response immunotherapy for hepatocellular carcinoma and viral hepatitis.
Hepatocellular carcinoma (HCC), chronic hepatitis B (CHB) and chronic hepatitis C (CHC) are characterized by exhaustion of the specific CD8(+) T cell response. This process involves enhancement of negative co-stimulatory molecules, such as programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte antigen-4 (CTLA-4), 2B4, Tim-3, CD160 and LAG-3, which is linked to intrahepatic overexpression of some of the cognate ligands, such as PD-L1, on antigen presenting cells and thereby favouring a tolerogenic environment. Therapies that disrupt these negative signalling mechanisms represent promising therapeutic tools with the potential to restore reactivity of the specific CD8(+) T cell response. In this review we discuss the impressive in vitro and in vivo results that have been recently achieved in HCC, CHB and CHC by blocking these negative receptors with monoclonal antibodies against these immune checkpoint modulators. The article mainly focuses on the role of CTLA-4 and PD-1 blocking monoclonal antibodies, the first ones to have reached clinical practice. The humanized monoclonal antibodies against CTLA-4 (tremelimumab and ipilimumab) and PD-1 (nivolumab and pembrolizumab) have yielded good results in testing of HCC and chronic viral hepatitis patients. Trelimumab, in particular, has shown a significant increase in the time to progression in HCC, while nivolumab has shown a remarkable effect on hepatitis C viral load reduction. The research on the role of ipilimumab, nivolumab and pembrolizumab on HCC is currently underway.
Elia Moreno-Cubero, Juan-Ramón Larrubia, Translational Hepatology Unit, Guadalajara University Hospital, University of Alcalá, E-19002 Guadalajara, Spain.
Elia
E
Moreno-Cubero
Elia Moreno-Cubero, Juan-Ramón Larrubia, Translational Hepatology Unit, Guadalajara University Hospital, University of Alcalá, E-19002 Guadalajara, Spain.
Juan-Ramón
JR
Larrubia
D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors* / Q000276:immunology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000276:immunology; D019698:Hepatitis C, Chronic / Q000276:immunology; D006801:Humans; D000074324:Ipilimumab; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000276:immunology; D000077594:Nivolumab; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors* / Q000276:immunology
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D000074324:Ipilimumab; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D000077594:Nivolumab
CD8+ T cells; Chronic viral hepatitis; Cytotoxic T-lymphocyte antigen-4; Hepatocellular carcinoma; Immune checkpoint modulation; Programmed cell death protein-1