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Feun et al.                                                                                                                                                               Immunotherapy for hepatocellular carcinoma

           A dose escalation study of the PD-1 inhibitor Nivolumab   An investigator-initiated, first in-human phase II trial of
           was initially reported at ASCO in 2015 and subsequently   the PD-1 inhibitor pembrolizumab was started at the
           updated at ASCO 2016.  [31]  In the initial report, 43   University of Miami (ClinicalTrials.gov NCT02658019).
           patients were treated in dose-escalation phase. Median   The dose of pembrolizumab is 200 mg intravenously
           of 6 (range 1-42) doses of Nivolumab administered.   every 3 weeks. So far, 10 patients have been treated.
           One dose-limiting toxicity (DLT) with grade 2 hepatic   It is too early yet to assess response. Correlative
           decompensation occurred at 10 mg/kg in uninfected   studies  include  tumor  staining  for  PD-L-1,  and
           cohort. No maximum tolerated dose was identified.   changes in hepatitis B and hepatitis C viral titers. In
           The 3 mg/kg dose was selected for dose expansion   addition, several representative cytokines associated
           in  uninfected  and  HCV-infected  cohorts. Thirty   with T-cell activation and suppression in serum and
           patients had discontinued therapy (26 patients due   peripheral blood mononuclear cells will also be
           to progressive disease, 2 due to complete response   analyzed pre- and post-treatment. T-cell proliferation
           (CR), 2 due to adverse events (1 due to increase in   and activation in response to T cell receptor (TCR) and
           bilirubin, 1 due to treatment-related increase in AST/  CD28 signals require IL-2, IL-12, IFN-g stimulation,
           ALT and hepatitis). Responses usually occurred within   but can be suppress by immunosuppressive cytokines
           3 months of drug initiation. The overall response rate   such as IL-10 and TGF-β. Changes in these cytokines
           was 15% (10% CR and 5% partial response, PR). The   may be important to predict response/toxicity to
           preliminary overall 1-year survival was 62%. This is   therapy.
           superior to the 1-year overall survival of 30% reported
           in phase III trials after sorafenib failure.       Dendritic cell vaccine
                                                              Another approach to immunotherapy is by infusion
           An update at ASCO 2016 showed the following: the   of autologous dendritic cell vaccine. [33]  Patients with
           dose escalation part involved 48 patients and the   advanced HCC were infused with mature autologous
           expansion part involved 214 patients. [32]  The dose of   dendritic cells pulsed ex vivo with a liver tumor cell
           nivolumab for the dose escalation ranged from 0.1 mg/kg   lysate and compared to a control group. There were
           to 10 mg/kg, while in the dose expansion study     15 patients in each group. In terms of response for
           nivolumab was given at 3 mg/kg every 2 weeks.      the treated group, 2 patients (13.3%) had partial
                                                              response, 9 (60%) had stable disease and 4 (26.7%)
           A total of 10 patients had HCV, 15 patients had HBV   patients had progressive disease. Serum gamma
           and 23 patients were uninfected. Safety data was   interferon and CD8+ T-cells both were increased after
           presented for 48 patients. Of these patients 79%   dendritic cell vaccination. The median survival time for
           had treatment-related adverse events (TRAEs) of    the treated group was 7 months versus 4 months for
           any grade, including 25 % with grade 3-4. The most   the untreated group. The side effects of the dendritic
           common TRAEs were rash, pruritus and elevation     cell vaccine were minimal with low-grade fever and
           of AST, ALT, lipase and amylase. AST and ALT and   mild bone aches.
           lipase/amylase occurred more frequently in this group
           of patients compared to other nivolumab-treated    Viral oncolytics
           patient populations. Most of these TRAEs were noted   A viral oncolytic immunotherapy approach has been
           to be asymptomatic and reversible. Five of 7 patients   studied using a vaccinia virus. [34-36]  These therapies
           responded within 3 months of start of treatment.   have been designed to replicate selectively within
                                                              HCC cells and produce cell lysis, while inducing tumor-
           Response was ongoing beyond 24 months in 1 patient   specific immunity. JX-594 (Pexa-Vec) is a vaccinia
           who stopped treatment with a complete response.    virus with a disrupted viral thymidine kinase gene with
           The median duration of response was 17 months,     insertion of human granulocytic-macrophage colony-
           range 6-24 months. Stable disease occurred out to   stimulating factor and β-galactosidase transgenes both
           12-18 months. Altogether, 3 patients had a complete   for immune stimulation and replication assessment.
           response and four had a partial response; the disease   A phase I trial of JX-594 demonstrated feasibility and
           control rate was 65%. The expansion phase was      tolerability and produced some responses. [35,36]  A
           continuing with nivolumab at 3 mg/kg. In conclusion,   randomized, dose finding trial was performed with direct
           Nivolumab has shown manageable safety and toxicity   infusion of the vaccinia virus into liver tumors (days 1,
           in HCC patients, including HBV and HCV infected    15 and 29). Patient survival duration was significantly
           patients. Antitumor activity was observed across all   longer with high dose (median 14.1 months) compared
           dose levels and cohorts. The response was durable in   to low dose (6.7 months). Responses were observed in
           many patients and the 1-year overall survival rate was   both injected and noninjected tumors within both dose
           encouraging.                                       groups.
            46                                                                                                      Hepatoma Research ¦ Volume 3 ¦ March 22, 2017
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