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Page 2 of 8 Bourinbaiar et al. Hepatoma Res 2020;6:2 I http://dx.doi.org/10.20517/2394-5079.2019.25

placebo group they rose. Clinical results are in line with in vitro observations indicating immune activation, as evidenced
by many-fold enhancement of CD69, Ki67, and INF-γ expression and at the same time marked anti-inflammatory effect
resulting in 10-fold decrease in TNF-α output and lack of influence on IL-2 production.

Conclusion: Hepcortespenlisimut-L, a tableted oral formulation derived from heat-inactivated pooled blood of patients
with HCC and viral hepatitis shows beneficial clinical effect, as demonstrated by improvement in liver function and
reduction of tumor marker AFP levels. These correlate with in vitro observations showing potent activation of the
immune response and pronounced oral tolerance effect.

Keywords: Hepatocellular carcinoma, alpha-fetoprotein, alanine transaminase, aspartate transaminase, IL-2, INF-γ,
TNF-α, CD69, Ki67, CD4, CD8, T lymphocytes

INTRODUCTION
Primary liver tumors originate from hepatocytes, cholangiocytes, and mesenchymal cells. Hepatoma
is generally defined as a cancer originating from liver cells. It is often called hepatocarcinoma or
hepatocellular carcinoma (HCC). It is the most common cancer of the liver, ranking as the second leading
[1]
cause of death from all types of cancers worldwide . Multiple risk factors have been identified including
chronic viral hepatitis, liver cirrhosis, non-alcoholic fatty liver disease (NASH), lifestyle factors comprising
alcohol abuse and smoking, metabolic diseases such as diabetes and obesity, environmental toxins such as
[2]
aflatoxin, and occasionally genetic and hereditary disorders . While the development of HCC is complex,
[3]
there is a consensus that the underlying cause is chronic inflammatory damage . Conventional treatment
with chemotherapy including sorafenib, regorafenib, lenvatinib, and cabozantinib is usually directed
[4]
at killing cancer cells - an approach that is quite toxic, leading to liver damage . This in turn leads to
hepatoma recurrence. Ideally, an effective HCC treatment must be two-pronged: in addition to destroying
malignant liver cells, normal liver cells must be spared from hepatotoxicity caused by treatment.
Immunotherapies are generally regarded as less toxic, although these toxicities can be life-threatening
[5]
if not managed promptly . The FDA has recently approved three antibody-based drugs: nivolumab,
pembrolizumab, and ramucirumab. Additional immune interventions from the checkpoint inhibitor PD
family, i.e., durvalumab, atezolizumab, and bevacizumab, as well as tremelimumab, which belongs to the
[6]
anti-CTLA4 class, are being investigated . Experience has shown that none of the currently approved
HCC drugs are free from adverse side effects, albeit with varying degrees of severity.

Hepcortespenlisimut-L (also known as Hepko-V5 or V5) is the immunotherapeutic drug from a novel class
[7]
that has been through Phase II trial . Anti-HCC property of V5 was discovered accidentally about ten
years ago during clinical use for original primary indications, which are chronic viral hepatitis and liver
[8,9]
cirrhosis . V5 has been commercially available since 2002, has been used by over 30,000 individuals, and
has never been reported of causing any serious adverse reactions. The US FDA granted Hepko-V5 orphan
drug designation status in 2014. The present paper provides preliminary data from the currently ongoing
Phase III trial and summarizes some of unpublished studies.

METHODS

Patients and treatment regimen
This Phase III placebo-controlled, 1:1 randomized trial was initiated with the goal of recruiting a total
of 120 patients with advanced HCC. The preliminary data from the initial batch of 30 enrolled patients
are provided to evaluate whether observed results confirm the data from an earlier published Phase II
[7]
open-label trial . All patients were in advanced stage of HCC and unfit for standard therapy, i.e., surgical
intervention, due to tumor size, its location, or multiplicity. Many patients had single or multiple events of
recurrent lesions after surgical intervention, such as resection, transarterial embolization, radiofrequency