Latest immunotherapy in liver cancer treatment

Liver cancer is currently the fifth most common cause of cancer-related death in the world. The current first-line systemic treatment drug is mainly sorafenib, but it usually only prolongs the overall survival by 3 months and has serious side effects.

In 2010, immunotherapy was first successful in melanoma. Since then, it has targeted the immunosuppressive molecule PD-1, programmed cell death-ligand 1 (PD-L1), and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). Monoclonal antibodies have been approved for listing one after another, breaking through the fortress of various solid tumors and bringing huge survival benefits to patients with advanced cancer, including hepatocellular carcinoma.

For example, data from stage I/II immune checkpoint inhibitors of advanced hepatocellular carcinoma show that the durable objective response rate for first-line and second-line use is about 20%. Clinical studies of anti-PD-1/anti-PD-L1 in combination with other checkpoint molecules are also underway. In addition to immune checkpoint inhibitors, other strategies for using the immune system, including CAR-T cell and NK cell therapy and peptide vaccines against hepatocellular carcinoma antigens, have also entered Phase I/II studies. Below we will systematically take stock for everyone.

Immune checkpoints are T cell surface molecules that can suppress or stimulate the immune system. Importantly, they are responsible for maintaining their tolerance and preventing unnecessary or excessive immune responses.

On September 22, 2017, based on a 214-person Phase 2 clinical trial, Checkmate-040, the US FDA approved the PD-1 antibody Opdivo for patients with advanced liver cancer who are resistant to NEXAVAR.

On November 9, 2018, the US FDA approved the immunotherapy drug pembrolizumab (Pembrolizumab, Keytruda) to treat patients with advanced liver cancer (hepatocellular carcinoma). It is suitable for patients with hepatocellular carcinoma who have previously been treated with too much Gemzar (sorafenib).

Several clinical trials of other anti-PD-1/anti-PD-L1 immunotherapies are currently underway. (Keynote-240, NCT02702401, and Keynote-394, NCT03062358) are two phase III clinical trials comparing Keytruda as a second-line treatment for advanced HCC patients with placebo.

In addition, several new immune checkpoint inhibitors, tislelizumab (anti-PD-1), camrelizumab (anti-PD-1), and durvalumab (anti-PD-L1), are currently being evaluated as second-line treatment response rates.

CTLA-4 is a CD28 homologue expressed on activated T cells. It suppresses T cell activation by competing for its ligand B7-1’s CD28, which transmits an immunostimulatory signal, and in turn delivers an inhibitory signal to T cells.

Tremelimumab (tisimumab) is the only anti-CTLA-4 antibody tested as monotherapy or combination therapy in the treatment of advanced HCC. A small pilot clinical trial of 20 viremia patients with hepatitis C virus (HCV)-related HCC showed that not only was the partial response rate of antitumor activity 17.6%, but it also showed antiviral activity and significant viral load reduction.

In addition to PD-1 / PD-L1 and CTLA-4, there are other inhibitory receptors, including T cell immunoglobulin mucin 3 (TIM-3) and lymphocyte activation gene 3 (LAG-3). Trials combining anti-PD-1/anti-PD-L1 therapy with drugs targeting TIM-3 (NCT03099109) and LAG-3 (NCT03005782 and NCT01968109) are already underway.

Although the response rate of single-agent treatment with immune checkpoint inhibitors has far exceeded the response rate of sorafenib, overall it is still very low (<20%). Therefore, in the clinic, we continue to explore strategies for maximizing patient response. For example, the combination of immune checkpoint inhibitors with other checkpoint inhibitors, small molecule kinase inhibitors, and other systemic and local treatments.

A phase I/II trial of the combination of durvalumab and tremelimumab for advanced liver cancer showed a response rate of 20% without any serious adverse events. A phase III study (NCT03298451) of this combination for first-line treatment is currently being recruited.

The synergy between immune checkpoint inhibitors and local therapies (including ablation, radiation therapy, and transarterial chemoembolization (TACE)) is also being investigated. Tumors with low mutation load and fewer new antigens are generally less immunogenic and have no/low response (or primary resistance) to checkpoint inhibitors. Local treatment and radiation therapy induce inflammation and produce new antigens that are released into the bloodstream. Therefore, the combination of checkpoint inhibitors and local area therapy is expected to increase sensitivity to checkpoint inhibitors.

In a preliminary study of 32 patients, tremelimumab was used in combination with radiofrequency ablation or TACE. Partial reactions are observed in up to 25% of patients.

The Global Oncologist Network’s medical department lists the current clinical trials of immunotherapy checkpoint inhibitor monotherapy and combination therapy in the following table for your reference. Those who want to participate can call the medical department for a preliminary evaluation.

T cells engineered with chimeric antigen receptors (CAR) gain the ability to recognize certain antigens, which allows specific cells (including tumor cells) to be targeted. CAR-T-based therapy has successfully treated CD19-positive hematological malignancies, which paved the way for its application in solid tumors. In HCC, Glypican-3 (GPC3) is most commonly used as a target for CAR-T therapy and has significant antitumor activity both in vitro and in vivo. Second, alpha-fetoprotein (AFP), which is usually overexpressed in HCC, is also used as a target and has a potent anti-tumor response. There are currently at least 10 phase I / II clinical trials (almost all conducted in China) to study the application of CAR-T cells in advanced HCC.

NK (natural killer cell) is the immune cell with the strongest anti-cancer effect. The most powerful place is that it can directly and quickly alien foreign bodies (viral and bacterial infections) without the process of antigen presentation and without other people reporting. Cells (cancer cells, senescent cells, etc.)

NK cells, like the “Molecular Patrol," patrol the bloodstream. Once they find foreign cells or mutant cells that have lost their self-identification (called MHC), the NK cell’s receptor immediately sends a signal and rushes to the target cell membrane. That is to say, the NK cells must be on the front line of the battle. It releases toxic particles, quickly dissolves the target cells, and causes the cancer cells to die within 5 minutes.

It should be noted that NK cells, as the core part of the immune system, are the most valuable innate immune cells in the human body, but they are very rare in human peripheral blood, accounting for only 5%-10% of lymphocytes. Cells account for 30-50% of lymphocytes in the liver of the human liver. Compared with circulating NK cells, NK cells in the liver have unique phenotypic characteristics and functional characteristics, showing higher cytotoxicity to tumor cells. During the occurrence of liver cancer, the proportion of NK cells and the function of cytokine (interferon-γ) production and cytotoxic activity are reduced. Therefore, therapies that reactivate NK cells and use them to attack tumors include chemoimmunotherapy and adoptive transplantation of NK cells. There are currently 7 phase I/II clinical trials investigating NK cell-based immunotherapy in HCC patients, most of which adopt adoptive transfer of autologous or allogeneic NK cells.

Cancer peptide vaccine is the same as CAR-T cell immunotherapy. The most studied peptide vaccine for hepatocellular carcinoma is GPC3 because it is overexpressed in up to 80% of liver cancers (including early tumors) but not in normal tissues. It is a very specific target. In addition, its expression is associated with a poor prognosis.

A preliminary phase I study of 33 patients with advanced HCC using the GPC3 peptide vaccine showed that the vaccine was well tolerated, 1 patient had partial remission (3%), and 19 patients had stable disease at 2 months (58%). Ninety percent of patients developed a cytotoxic T lymphocyte response after induction with a specific GPC3 vaccine, which was associated with overall survival. The combined use of the GPC3 peptide vaccine and other therapies is currently being further explored.

We have entered a new era in the treatment of hepatocellular carcinoma, in which strategies based on immune checkpoint inhibitors will soon become the basis, either as monotherapy or in combination with other checkpoint inhibitors and kinase inhibitors. In addition, new Immunotherapy research and development has also brought more hope and treatment options to advanced patients. Because there are too many clinical trials, it is impossible to introduce them one by one in this article.