ILCA Symposium 1: Emerging Concepts for Understanding Liver Cancer
Chairs: Irene Ng, MD, PhD (Hong Kong) and Curtis Harris, MD, PhD (USA)
'Immune Response in HCC and Opportunities for Treatment'
Tim Greten, MD (USA)
HCC represents a typical inflammation associated cancer. Patients with chronic viral hepatitis are at increased risk to develop HCC. Hepatitis B infection has been shown to reduce the incidence of HCC in Taiwan and may be considered as the first cancer vaccine. Multiple investigators have demonstrated that analysis of the tumour microenvironment may be used to predict patients’ outcome demonstrating a pivotal role of local immune responses in this disease. While the liver is considered to be a site inducing immune tolerance, spontaneous tumour-specific immune responses can frequently be detected in patients with HCC. One reason why these immune responses fail to provide significant anti-tumour effects may be the presence of immune suppressor mechanisms such as an accumulation of CD4+ regulatory T cells and CD14+HLA-DRlo myeloid derived suppressor cells. While surgery, radiation and systemic cytotoxic chemotherapies dominate as treatment options for patients with solid cancer, the situation is very different in HCC, where loco-regional treatments are widely applied. Such treatments induce rapid tumour cell death and modulate anti-tumour immune responses, which may favor or impair patients’ outcome. Systemic treatment options are limited, which make immunotherapy a potentially interesting treatment alternative in HCC. Recent immunotherapy studies demonstrating promising results include trials evaluating intra-tumour injection of an oncolytic virus expressing GM-CSF, glypican 3 targeting treatments and anti-CTLA4 treatment. While some of the approaches may provide benefits as single agents, future studies are needed to test these treatments in combination treatments considering the specific treatment modalities for patients with HCC.
Exploring Resistance to Targeted Therapies in Cancer
Ghassan Abou-Alfa, MD (USA)
Since sorafenib has been approved as a standard of care for the treatment of advanced hepatocellular carcinoma (HCC) there has been ever-increasing interest in exploring single or multiple agent venues to help further improve medial overall survival of patients with advanced HCC. Disappointingly several single agent anti-angiogenics as well as a combination of sorafenib plus erlotinib have failed so far the median overall survival beyond the close to 10 months ceiling of sorafenib. A possible synergy between sorafenib plus doxorubicin is awaiting evaluation in a randomised phase III study and a phase II in the first line and second line settings respectively. Apparent differences in outcome based on etiology and ethnicity with sorafenib raise the possible importance of its mutli- targeted nature, including raf-kinase inhibition. The advent of c-met inhibitors cabozantinib and tivantinib have opened another option to bypass the alleged anti-angiogenic ceiling and brought the concept of enriched high c-met population to the arena of treating HCC. While this flurry of research activity has been met with disappointment, we are undoubtedly closer to a custom-based therapy in treating advanced HCC that should soon lead to advances through the anti-angiogenic ceiling.
Understanding the Pathogenesis of Cholangiocarcinoma
Tushar Patel, MD (USA)
Intrahepatic cholangiocarcinoma (iCCA) and hilar cholangiocarcinoma (hCCA) are aggressive malignancies with a very poor prognosis. The mechanisms involved in the pathogenesis of these cancers are not well understood. Recent epidemiological, laboratory-based and genome-wide profiling studies have provided major new insights into the pathogenesis of these tumours. New knowledge is emerging from recognition of their distinct and separate nature, as well as definition of specific risk factors, genetic alterations and molecular events that are associated with these two different tumour types. The inter-related roles of genetic changes, inflammation and microenvironmental influences are emphasised by aberrant activation of pathways of importance in disease pathogenesis, such as NOTCH, IL-6/STAT, hepatocyte growth factor/MET, epidermal growth factor, vascular endothelial growth factor and KRAS / mitogen-activated protein kinase and others. These new insights into the pathogenesis of these tumours offer several opportunities for improved molecular diagnosis and therapy.