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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