Immuno-Oncotherapeutic Approaches in Advanced Hepatocellular Carcinoma

Abstract

Advanced hepatocellular carcinoma has limited treatment options, but there has been extensive growth recently with cabozantinib, regorafenib, lenvatinib, nivolumab, atezolizumab, and bevacizumab, which are some of the treatments that have received FDA approval just over the last three years. Because HCC tumor microenvironment is potentially immunogenic and typically characterized by inflammation, immunotherapy has been proposed as a potential novel therapeutic approach, which has prompted studies in advanced HCC patients investigating various immune-therapeutic strategies such as CAR-T cell therapy, checkpoint inhibitors, and onco-vaccines. The anti-PD-1 checkpoint inhibitors nivolumab and pembrolizumab have been FDA approved as a second line treatment in patients who progressed or are intolerant to Sorafenib. To build up on the success of PD-1 monotherapy, combinatorial regimens with PD-1/PD-L1 inhibitors plus VEGF targeted agents have shown positive results in various malignancies including HCC. The combination of atezolizumab plus bevacizumab is the new addition to the HCC treatment armamentarium following a pivotal study that demonstrated an improvement in OS over frontline sorafenib. Other novel immune-based approaches and oncolytic viruses are in the early phases of clinical evaluation. These innovative approaches enhance the intensity of cancer-directed immune responses and will potentially impact the outlook of this aggressive disease.

Bioinformatic Analysis of Key Genes Related to Tumor Microenvironment in Hepatocellular Carcinoma

“…Because HCC TME is potentially immunogenic and typically characterized by in ammation, immunotherapy has been proposed as a potential novel therapeutic approach, which has prompted studies on various immuno-therapeutic strategies in advanced HCC patients. Therapies like chimeric antigen receptor T (CAR-T) cell therapy, checkpoint inhibitors, and onco-vaccines have shown promising results [25]. These studies were focused on a speci c target provided by either experimental results or novel discovered genes from data analysis.…”

Hepatocellular Carcinoma: An Overview of the Changing Landscape of Treatment Options

“…Therefore, at present, numerous clinical trials are underway. [82][83][84] Remarkably, a Phase I trial of the combination of pembrolizumab and lenvatinib, which was well tolerated with promising anti-tumor activity in patients with unresected HCC. 85,90 Furthermore, it is worth mentioning that there are two ongoing phase III studies, the COSMIC-312 study and the HIMALAYA study, in which combination regimens are being evaluated.…”

“…As already mentioned, not only has immunotherapy been tested as monotherapy, but it has also been incorporated in combination regimens in a plethora of ongoing trials. [79][80][81][82][83][84][85][86][87][88][89][90] A striking example is the combined treatment of nivolumab plus ipilimumab, which led to significant objective response rates (ORR: 32%) and durable responses, but it also revealed increased toxicity compared to monotherapy with nivolumab (ORR: 14%). However, the combination regimen (nivolumab 1mg/kg plus ipilimumab 3mg/ kg every 3 weeks for 4 cycles and then nivolumab 240mg every 2 weeks) received accelerated approval in the USbased on the phase III CheckMate-040 clinical trial.…”

Natural Killer–Dendritic Cell Interactions in Liver Cancer: Implications for Immunotherapy

“…DC-targeting immunotherapeutic strategies include DC vaccination, in vivo DC expansion, and in vivo DC reprogramming [ 203 ]. DC vaccination with exogenously expanded and activated autologous DCs was proven to have low toxicity but low efficacy in advanced HCC in different clinical trials, likely because the immunosuppressive TME circumvents the effects of immunotherapy [ 204 , 205 , 206 ]. Oncolytic immunotherapies, aimed at recruiting and activating DCs at the tumor site and triggering antitumor immune responses, provided disappointing results in HCC patients [ 204 ].…”