Checkpoint inhibition in hepatocellular carcinoma: Outsmarting the Squid Game

The premise behind Squid Game, Netflix’s most viewed show to date, is a brutish contest where 456 bankrupted individuals risk their lives playing deadly children’s games for a chance to win an exorbitant money prize. The acclaimed series captures, on the silver screen, the plight of desperation and the willingness to sacrifice everything in the hopes for a cure to a bleak financial outlook. The show’s global success is perhaps attributable to its profound resonance with financial struggle, socio-economic disparities, and the quintessential tenets of human resilience. At its crux, Squid Game is a social commentary about survival, and the extreme lengths one may endure to not only live, but to prosper. Beyond a prima facie analysis, the Squid Game may indeed be an apt analogy for hepatocellular carcinoma (HCC) treatment.

The first objective of any cancer treatment is, of course, to prolong survival. In the world of HCC, the ultimate Squid Game is its management. The brave player (ie, the patient diagnosed with advanced HCC beyond surgical cure) seeks to survive despite all odds—and is ready and willing to sacrifice everything to succeed. HCC therapy, therefore, is the Squid Game she must manoeuvre to survive, and her survival depends on the innovativeness of therapies to defeat HCC—its ability to grow, mutate and metastasize, and ultimately kill the host. Such survival strategies rival those employed by the players of the Squid Game, who seek innovative solutions to ensure livelihood.

Analogous to the impact of direct active antivirals for hepatitis C treatment, immune checkpoint inhibitors (ICIs) have dramatically altered the landscape of oncology, and our fundamental understanding and approach to cancer treatment (1). ICIs thus allow the Squid Game player to potentially bypass the Front Man, thereby possibly charting the pathway to success. After having demonstrated effectiveness in tumours ranging from melanoma to lung cancer, ICI is increasingly being studied for HCC—a disease which is the second leading cause of cancer related death around the world, and for which highly effective treatments are still lacking.

Unfortunately, traditional chemotherapy is not helpful in HCC due to high potent expression of chemo-resistant genes such as p53, p-glycoprotein, glutathione S-transferase and heat shock proteins (hsp) (1). Furthermore, the underlying liver dysfunction of cirrhotics with HCC renders many patients highly susceptible to dangerous hepatotoxicity of traditional chemotherapies. Ascertaining treatment effectiveness either in clinical trials or the real world, is made more challenging by the fact that patients with advanced HCC usually have cirrhosis, which in and of itself may determine, or at least heavily influence, mortality. The cirrhotic HCC patient, therefore, is in a position much like the protagonist of Squid Game—conventional solutions in the face of bleak financial distress seem inappropriately tailored to the magnitude of the problem at hand.

HCC treatment is complex, and to a certain extent, is centre-dependent since it hinges on local expertise and necessitates multidisciplinary care. The main player, to continue the Squid Game analogy, relies on a supportive team, and is led by the hepatologist, who is often the physician offering appropriately timed screening and early detection. The hepatologist must also manage the patient’s underlying liver disease in close partnership with the medical team of oncologists, interventional radiologists, hepatobiliary surgeons, and/or transplantologists. Although there are many staging and treatment algorithms for HCC used around the globe, the Barcelona Clinic Liver Cancer (BCLC) is the most used system, generating a treatment approach upon stratifying patients into early, intermediate, and advanced HCC stages (2,3). A cure to HCC can be achieved from resection, ablation or transplantation, but is unfortunately only feasible for early stage HCC (4). Studies are ongoing but not affirmative at this juncture to determine if ICIs may be useful in the adjuvant setting for patients with early HCC who are nevertheless at high risk of recurrence (5,6,7,8).

Where ICIs may have their most useful application, however, is in intermediate and advanced stage HCC (1). These stages mandate locoregional and/or systemic therapies, either alone or in combination. The story of systemic treatment development in HCC is laggard to say the least. Systemic treatment was not available for HCC until 2008 with the molecularly targeted tyrosine kinase inhibitor (TKI) sorafenib which resulted in marginal improved survival of about three months over supportive care (9). A full decade later, the REFLECT trial demonstrated that a second TKI, Lenvatinib, is comparable in impact to sorafenib (10). For patients who do not respond to the aforementioned TKIs, second line multikinase inhibitors regorafenib, cabozantinib, or ramucirumab are all viable options though with minimal impact on mortality rates (1). With TKIs being ineffectual agents at markedly extending overall survival, liver cancer patients and physicians alike were thus very hopeful immunotherapy would improve outcomes in patients with advanced HCC. Thankfully, there is great reason to be excited about ICIs in HCC management, oft viewed as the greatest advent in the field since direct acting antiviral agents for hepatitis C.

HCC may be susceptible to ICI due to its unique immunogenic microenvironment. As our colleagues in transplant are well aware, the liver has a unique immune tolerability due to its constant exposure to antigens. It’s very peculiar immune-privileged milieu makes ICIs a potential match made in heaven to HCC, especially since HCC is an inflammation-induced cancer. ICIs may be the hidden weapon the Squid Game player needs to succeed. ICIs are a class of monoclonal antibodies that block immune checkpoints which are expressed in many cells such as natural killer cells, dendritic cells, tumour associated macrophages, monocytes, and B and T cells. ICIs effectively facilitate T cells to kill cancer cells, without destroying non-cancer tissues. The important immune receptors targeted by ICIs are CTLA-4, PD-1, TIM-3, BTLA, VISTA, LAG-3, and OX-40 (1).

Per current guidelines, patients with intermediate HCC should be considered for transcatheter arterial chemoembolization (TACE) (4). Unfortunately, trials evaluating TACE with sorfenib did not improve survival as compared with TACE alone (11). In patients with intermediate HCC, evolving evidence shows that the combination of ICIs and TACE may be superior to TACE alone (11,12). Likewise, systemic treatments are indicated for patients with advanced HCC not eligible for locoregional therapies or after progression of the former. Presently, the best available first-line treatment for advanced HCC is atezolizumab, a PDL-1 blocker, with bevacizumab, a VEGF blocker (5). It is amazing to reflect that today, all phase-3 trials evaluating systemic therapy for treatment-naïve patients with HCC involve ICIs (14). While it is beyond the scope of this commentary to review all of the ICI trials in HCC, the PD1 and PDL1 inhibitors are the mainstay on systemic therapies for HCC at the present time (eg, nivolumab, pembrolizumab) producing impressive increases in overall survival, 15%–20% remission rates, and even a 1%–5% complete response rate (1). It appears that ongoing clinical trials are now evaluating a number of combination strategies in HCC, including ICIs with the use of CTLA-4 inhibitors, VEGF inhibitors, and multi-TKIs. Notwithstanding the vast range of immune-mediated adverse events, ICIs represent an exciting step forward in the management of HCC.

Immunotherapy is a new frontier for HCC management, changing the landscape but also necessitating novel pathways for innovation which must still be mapped out. Alas, just as in the Squid Game where victory is not guaranteed to the player, so too do we find that only a minority subset of patients with HCC benefit from monotherapy with ICIs. The Squid Game of HCC management requires innovative strategies to win. While it is clear that combination therapy may be a wiser approach, thereby targeting different cancer pathways, we have much to learn and discover. Liver cancer treatments must therefore focus on the many pathways for tumour development, proliferation, and metastatic spread. These pathways include cell cycle arrest, apoptosis, and metastasis. Very much like the nature of the Squid Game, effective HCC treatment must be ruthless to the tumour without harming the host, with the aim of therapy to cut the beast within cancer by severing the tentacles of the squid, rendering it ineffective and defenceless. To checkpoint inhibitors, we say, Godspeed.

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No funding was received for this work.

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The authors have nothing to disclose.

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This article has been peer reviewed.

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