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Page 2 of 12 Armstrong et al. Hepatoma Res 2021;7:18 I http://dx.doi.org/10.20517/2394-5079.2020.118

as cirrhosis and chronic hepatitis. The most common risk factors include hepatitis B (HBV), hepatitis C
[3,4]
(HCV) fatty liver disease such as nonalcoholic steatohepatitis (NASH), and alcohol consumption .

[5,6]
In western countries, only about 30% of HCC patients are diagnosed at an early stage . Improvements
in screening and surveillance techniques and the development of antiviral therapies have led to protection
[7]
against HCC in high-risk patients . Early detection of HCC offers the best prognosis and overall survival
(OS) due to the option of curative treatment in the form of resection or liver transplantation [7-10] . Curative
resection may be offered to patients, no matter the HCC size, as long as liver function is adequate -
Child-Pugh Class A without portal hypertension and residual liver volume of at least 20% [8,10] . Liver
transplantation is the preferred treatment choice for patients who fall within the Milan Criteria (single
lesion of ≤ 5 cm or up to 3 lesions of ≤ 3 cm) [9-13] . For patients who are not diagnosed within the criteria
for a liver transplant, liver-targeted therapies such as radiofrequency ablation (RFA), transarterial
chemoembolization (TACE) and Y90 radioembolization (Y90-RE) are used to control HCC progression
and prolong the survival rate of patients [14,15] .

Unfortunately, many patients with HCC are diagnosed at more advanced stages, involving multifocal
disease, vascular invasion and extrahepatic spread of the cancer. Such cases require systemic therapy, and
until late 2007, there were no treatment options for these patients. In November 2007, initial results from
[16]
2 investigations of sorafenib in the treatment of patients with hepatocellular carcinoma - the SHARP
[17]
and Asia-Pacific trials - both randomized placebo-controlled Phase III trials, resulted in the approval
of sorafenib, a tyrosine kinase inhibitor (TKI), as the first systemic therapy for advanced unresectable
HCC. Patients in these trials received either daily sorafenib or placebo in the frontline until radiological
or symptomatic progression was noted. Both studies reported significantly increased OS of the sorafenib
compared to the placebo-treated cohort.

Now, in 2020, nine systemic therapeutic agents are available to treat patients with HCC, including
sorafenib, lenvatinib, and combinations of bevacizumab plus atezolizumab in the frontline; and regorafenib,
nivolumab with or without ipilimumab, cabozantinib, ramucirumab and pembrolizumab in the second-line
setting [16-24] . Although this is a significant improvement compared to a decade ago, there is limited data on
how to sequence treatments for maximal survival benefit to patients.

The use of immune checkpoint inhibitors alone or in combination with targeted therapies generates durable
responses that have reshaped the treatment landscape for HCC. The rationale behind using immunotherapy
in advanced HCC lies in the knowledge that these tumors arise from a background of chronic inflammation
and from case reports of spontaneous HCC remission after removing immunosuppressive agents [25-27] . The
more complex reasoning to utilize immune checkpoint blockade is discussed below. As immunotherapy
expands treatment options for HCC and numerous other malignancies, biomarkers of response for
prediction and monitoring purposes are needed. In the current literature, higher response rates to
immunotherapy have been seen in inflamed tumors with a high degree of cytotoxic T-cell infiltration and
proinflammatory cytokines, PD-L1 expression, tumor mutational burden (TMB), microsatellite instability
and deficient DNA mismatch repair. However, biomarker data for HCC is not yet well established [28-32] .

RATIONAL BEHIND IMMUNOTHERAPY IN HCC
The concept of immunotherapy is the mobilization of a patient’s immune system to fight cancer. Hence,
as malignant cells arise in the body due to epigenetic and genetic factors, continued immune surveillance
[33]
recognizes neoantigens on these transformed cells and activates the immune system to clear them .
However, at the same time, malignant cells develop multiple resistance mechanisms to evade immune
recognition and destruction. They promote the release of immunosuppressive mediators like transforming
growth factor-beta (TGF-β) and interleukin 6 (IL-6), which contribute to cancer cell growth, and cytokines