Challenges and Opportunities in the Clinical Development of Immune Checkpoint Inhibitors for Hepatocellular Carcinoma

Abstract

After a decade of stagnation in drug development, therapeutic reversal of immune-exhaustion with immune checkpoint inhibitors (ICPIs) has been shown to be effective in advanced hepatocellular carcinoma (HCC). The clinical development of novel ICPIs continues at a rapid pace, with more than 50 clinical trials of immunotherapeutic agents registered as of May 2018 for this indication. The development of ICPI is particularly challenging in patients with HCC, a population with unique features which impact on safety and efficacy of immune-modulating therapies. In this review, we discuss the biological foundations supporting the development of ICPIs across the advancing stages of HCC, focusing on the rational positioning of ICPIs across the various Barcelona-Clinic Liver Cancer (BCLC) stages of the disease. Translational studies should guide adequate prioritization of those therapeutic agents and combination strategies which are most likely to achieve patient benefit based on solid mechanistic and clinical justifications. (Hepatology 2019;69:2258-2270).T he role of immune evasion as a pivotal mechanism in the progression of hepatocellular carcinoma (HCC) has long been recognized, but has for many decades remained an "undruggable" domain attributed to the lack of effective therapies capable of reversing cancer-related immunosuppression. (1) Clinical trials of immune checkpoint inhibitors (ICPIs) have ascribed HCC to the expanding list of tumors characterized by intrinsic sensitivity to immunotherapy. In particular, these agents have been proven effective in advanced melanoma, renal cell carcinoma, and non-small-cell lung cancer (NSCLC), with an increasing number of studies demonstrating response rates of up to 25% across hematological and solid malignancies. However, despite the unprecedented efficacy of ICPIs, patients with HCC represent a population with distinct features. The concomitant presence of cirrhosis in >80% of patients is unique and deserves to be considered for its potential safety impact on the delivery of immunotherapy.In terms of efficacy, the presence of a predominantly immunosuppressive microenvironment within

Identification of Tumor Mutation Burden and Immune Infiltrates in Hepatocellular Carcinoma Based on Multi-Omics Analysis

“…Immunotherapy is the use of drugs to promote immune cell in ltration in the tumor microenvironment leading to the killing of the tumor cells by T or B lymphocytes. The most common rst-line treatment for HCC is sorafenib, which has been proven to prolong the survival of patients with HCC for several months [22,23]. Immunotherapy mainly includes tumor vaccines, biological therapy, CAR-T cells, and immune checkpoint inhibitors (PD-1, CTLA-7).…”

Immune-based therapies for hepatocellular carcinoma

“…In the specific context of HCC, anti-tumour immune reconstitution with ICPIs has produced initial enthusiasm based on preliminary results from single-arm studies [8,9], suggesting evidence of anti-tumour activity. With immunotherapy rapidly expanding as a novel option in the treatment landscape of HCC [10], we discuss the rationale for the development of immune-based therapies in liver cancer and review the basic immune-biologic mechanism that underlie the progression of HCC and might be exploited for therapy.…”

HSP4 triggers epithelial‐mesenchymal transition and promotes motility capacities of hepatocellular carcinoma cells via activating AKT

“…Hepatocellular carcinoma (HCC) ranks the fifth highest incidence worldwide and remains the third major cause of death globally 1‐4 . Concurrently, radical resection is considered as the only approach for curing HCC, however, the clinical outcome remains unsatisfactory because of high incidence of metastasis or recurrence 5‐7 . As evidence, about half of HCC patients suffered relapse after surgery, and recurrence/metastasis is responsible for most HCC associated morbidity and mortality after resection 8‐11 .…”