Alsinet, Clara

Hernandez-Gea, Virginia

Llovet, Josep M.

Elsevier - Publisher Connector 

International HepatologyOncolytic immunotherapeutic virus in HCC: Can it compete
with molecular therapies?
Virginia Hernandez-Gea1, Clara Alsinet1, Josep M. Llovet1,2,3,⇑
1HCC Translational Research Laboratory, Barcelona-Clínic Liver Cancer Group, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS),
Hospital Clínic de Barcelona, Universitat de Barcelona (UB), Barcelona, Catalonia, Spain; 2Mount Sinai Liver Cancer Program,
Division of Liver Diseases, Ichan School of Medicine at Mount Sinai, New York, NY, USA;
3Institució Catalana de Recerca i Estudis Avançats, Barcelona, Catalonia, SpainCOMMENTARY ON:
Randomized dose-ﬁnding clinical trial of oncolytic immuno-
therapeutic vaccinia JX-594 in liver cancer. Heo J, Reid T, Ruo
L, Breitbach CJ, Rose S, Bloomston M, Cho M, Lim HY, Chung
HC, Kim CW, Burke J, Lencioni R, Hickman T, Moon A, Lee YS,
Kim MK, Daneshmand M, Dubois K, Longpre L, Ngo M, Rooney
C, Bell JC, Rhee BG, Patt R, Hwang TH, Kirn DH. Nat Med 2013
March;19(3):329–36. Copyright (2012). Abstract reprinted by
permission from Macmillan Publishers.
http://www.ncbi.nlm.nih.gov/pubmed/23396206
Abstract: Oncolytic viruses and active immunotherapeutics have
complementary mechanisms of action (MOA) that are both self
amplifying in tumors, yet the impact of dose on subject outcome is
unclear. JX-594 (Pexa-Vec) is an oncolytic and immunotherapeutic
vaccinia virus. To determine the optimal JX-594 dose in subjects with
advanced hepatocellular carcinoma (HCC), we conducted a random-
ized phase 2 dose-ﬁnding trial (n = 30). Radiologists infused low- or
high-dose JX-594 into liver tumors (days 1, 15, and 29); infusions
resulted in acute detectable intravascular JX-594 genomes. Objective
intrahepatic Modiﬁed Response Evaluation Criteria in Solid Tumors
(mRECIST) (15%) and Choi (62%) response rates and intrahepatic
disease control (50%) were equivalent in injected and distant
noninjected tumors at both doses. JX-594 replication and
granulocyte–macrophage colony-stimulating factor (GM-CSF)
expression preceded the induction of anticancer immunity. In
contrast to tumor response rate and immune endpoints, subject
survival duration was signiﬁcantly related to dose (median survival
of 14.1 months compared to 6.7 months on the high and low dose,
respectively; hazard ratio 0.39; P = 0.020). JX-594 demonstrated
oncolytic and immunotherapy MOA, tumor responses and dose-
related survival in individuals with HCC.
 2013 European Association for the Study of the Liver. Published
by Elsevier B.V. Open access under CC BY-NC-ND license.Journal of Hepatology 20
Keywords: Hepatocellular carcinoma; Oncolytic virus; Immunotherapy.
Received 2 May 2013; accepted 5 May 2013
⇑ Corresponding author. Address: HCC Translational Research Laboratory, BCLC,
IDIBAPS-Hospital Clínic, Rosello 153 (Centre Esther Koplowitz, 3rd Floor), 08036
Barcelona, Spain. Tel.: +34 932279155; fax: +34 932275792.
E-mail addresses: jmllovet@clinic.cat, Josep.Llovet@mssm.edu (J.M. Llovet).HCC is a major public health problem, ranking as the 3rd
cause of cancer-related death and the 16th absolute cause of
death globally [1]. Its incidence is rising worldwide and besides
major improvements in HCC management during the past
30 years, sorafenib remains the only approved systemic treat-
ment for advanced tumors [2]. Considering that no biomarkers
are able to predict response to sorafenib [3] and recent trials in
ﬁrst and second line have not provided treatment alternatives
[4], the development of novel and innovative therapies is crucial
[5,6].
The study from Heo et al. points towards a completely new
potential treatment option for HCC. The JX-594 virus has an
inactivation of its thymidine kinase further engineered to express
b-galactosidase, a surrogate marker for detecting viral gene
expression and human granulocyte–macrophage colony-stimu-
lating factor (GM-CSF) to stimulate anti-tumor immunity [7,8].
Replication of the virus is dependent on the EGFR–RAS pathway,
achieving a satisfactory high local concentration in the tumor due
to selective targeting of tumor cells. JX-594 infects cells with
activation of the EGFR/RAS pathway and uses the pathway to rep-
licate and eventually kill the infected cells (Fig. 1) [7,8].
The study is a dose ﬁnding trial in which the authors com-
pared low-dose (108 plaque-forming units (PFU)) versus high
dose (109 PFU) intratumoral delivery of JX-594 virus in 30
patients with advanced HCC. Thus, low dose patients are receiv-
ing 10% of the viral load compared to high-dose patients. The trial
is a multicenter randomized 1:1 trial assigning patients to receive
either high or low dose, stratiﬁed by viral or non-viral infection.
JX-594 virus was administered by imaging-guided intratumoral
injection on day 1, 15, and 29 and the dose was distributed
among up to ﬁve intrahepatic tumors. The objectives of this trial
were to compare safety and efﬁcacy measured as response rate
assessed by expert radiologist blinded to treatment group and
overall survival. Concentration of JX-594 in the blood was maxi-
mum 15 min after injection and virus replication was assessed by
b-gal levels and hGM-CSF induction together with detection of
JX-594 genomes in the blood followed by induction of humoral
and cellular anticancer immunity. Both doses were well-tolerated
and no treatment-related deaths were reported, being the most
frequent adverse event ﬂu-like symptoms in all subjects, and
the most severe adverse event lymphopenia (grade 3–4) in 14%
of patients in both treatments groups. Serial dynamic magnetic
resonance imaging scans were used to assess tumor response13 vol. 59 j 882–884
Tumor
cells
Tumor cells
hGM-CSF
EGFR
Extravasation
JX-594
Liver
PP
Ras
Nucleus
Immune
response 
Cell death
Direct viral
replication
DC
T cells
Oncolysis
Tumor
cells
Tumor
blood vessels
PP
Nearby 
tumor cell
Fig. 1. JX-594 mechanism of action and tumoral selectivity. Genetically-modiﬁed viral particles (JX-594) are capable of replicating inside the tumor cell with active
EGFR–RAS kinase pathway. After replication, viral-induced oncolysis triggers tumor cell death. At the same time, JX-594 expresses GM-CSF which triggers immune-induced
cell death.
JOURNAL OF HEPATOLOGYby mRECIST and Choi response, achieved in around 15% and 62%
of patients, respectively. Patients in the high dose group had sig-
niﬁcantly better overall survival (OS) (14.1 months vs.
6.7 months). The study was halted early because of these survival
differences.
The study deserves special attention due to several positive
aspects. First, this is a novel treatment approach with a triple
mechanism of action: (1) direct viral replication inducing oncol-
ysis of cancer cells with activated Ras signaling, (2) immunother-
apeutic, due to the expression of GM-CSF by the virus, which
stimulated toll-like receptors, activating dendritic cells and the
whole immune response related to T-cell activation [7,8], and
(3) anti-angiogenic properties [7,8]. Second, the treatment is
quite selective targeting tumoral cells. This phenomenon is
explained both due to the fact that tumoral blood vessels allow
extravasation of the viral particle [8] – as opposed to normal ves-
sels – and also due to the selective replication in cells showing
activation of Ras, very uncommon in normal cells. In addition,
the group nicely demonstrated, in a phase I trial, that intravenous
injection of the JX-594 virus selectively target cancer tissue with-
out affecting normal tissues in patients with advanced, treat-
ment-refractory solid tumors [7]. Its ability to spread within
the tissue carrying large therapeutic transgenes and its stability
in the blood, made the JX-594 a good candidate for intravenous
infusion, as well. Third, the studies have shown lack of severe
toxicity or treatment-related death cases. This is particularly
important considering that more than 80% of patients with HCCJournal of Hepatology 201have cirrhosis, and thus non-tumoral toxicity may induce liver
failure, as has been reported with sunitinib therapies [9]. Finally,
tumoral lysis was detected in cancer cells not-directly inoculated
with the oncolytic virus, suggesting effective mechanisms result-
ing from immune response or distant viral replication. Thus, the
approach looks promising and results from additional studies are
expected.
The oncolytic virus therapeutic approach reported has also
some limitations. First, the authors did not include sorafenib or
placebo as control arm for ﬁrst or second-line therapies, respec-
tively. It is obvious that they aimed at exploring a dose-
dependent effect, which seems identiﬁed with the higher dose,
but the median 14.1 months of survival of the active arm is
difﬁcult to put in context. Although most of the patients had
advanced disease (BCLC C), some of them already received sorafe-
nib as ﬁrst line therapy, and thus mixed populations have been
included. The randomized nature of the study aids in deﬁning a
median survival for the control arm (low-dose therapy) of
6.7 months. The study is clearly underpowered to establish
survival beneﬁts, but the data can be interpreted in the context
of previously reported large-phase III investigations. Overall
survival reported from sorafenib trials in ﬁrst line established a
median survival of 10–11 months, whereas this ﬁgure can
decrease to 8–9 months in second line studies, as the BRISK
trial, which included patients who failed or were intolerant to
sorafenib and evaluated the effect of brivanib in second line
[10]. Therefore, although a random error effect cannot be3 vol. 59 j 882–884 883
International Hepatology
discarded, we consider the survival reported as a signal of efﬁ-
cacy, which needs further consideration.
Once established that the results reported in Nature Medicine
represent a signal of efﬁcacy, the question is now how further
research needs to be moved forward. It seems that the high dose
is adequate in achieving anti-tumoral and OS effects without
major toxicities. The limitation of intratumoral-only administra-
tion can be overcome by testing the effect of a combined
JX-594 systemic administration (clinicalTrials.gov, NCT01636284).
Nonetheless, the critical question is whether the therapy should
be moved ahead in ﬁrst vs. second line. Data on the combination
with sorafenib is not available so far, and would be crucial for
further exploring this path in ﬁrst line. Alternatively, ongoing
trials in second line comparing high-dose vs. placebo/best sup-
portive care in patients who failed to sorafenib (clinicalTrials.gov,
NCT01387555) can provide additional evidence for decision-
making. A ﬁnal approach would be to select biomarkers deﬁning
a speciﬁc target population, for instance those patients with RAS
activation. Nonetheless, in this speciﬁc case trial enrichment
would have a minor impact since at advanced HCC stages Ras
activation seems universal [11], as opposed to what has been
described at more early phases of the disease [12].Conﬂict of interest
Dr. Llovet has a consultancy agreement with Jennerex.
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Oncolytic immunotherapeutic virus in HCC: Can it compete with molecular therapies? 

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Oncolytic immunotherapeutic virus in HCC: Can it compete with molecular therapies?

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