Utilization of Immunotherapy for the Treatment of Hepatocellular Carcinoma in the Peri-Transplant Setting: Transplant Oncology View

Abstract

Hepatocellular carcinoma (HCC) represents the second most common cause of cancer-related deaths and accounts for over eighty percent of primary liver cancers worldwide. Surgical resection and radiofrequency ablation in small tumors are included in the treatment options for HCC patients with good liver function profiles. According to the Milan Criteria, only a small portion of HCC patients are eligible for liver transplantation due to advanced-stage disease and large tumor size preventing/delaying organ allocation. Recently, the use of anti-programmed cell death protein 1 and programmed cell death ligand 1 (PD-1 and PD-L1) checkpoint inhibitors in the treatment of cancers have evolved rapidly and these therapies have been approved for the treatment of HCC. Immune checkpoint inhibitors have resulted in good clinical outcomes in pre-and post-transplant HCC patients, although, some reports showed that certain recipients may face rejection and graft loss. In this review, we aim to illustrate and summarize the utilization of immune checkpoint inhibitor therapies in pre-and post-liver transplants for HCC patients and discuss the assessment of immune checkpoint inhibitor regulators that might determine liver transplant outcomes.

Keywords: CTLA-4 inhibitors; PD-1 inhibitors; allograft rejection; hepatocellular carcinoma; immune checkpoint inhibitors; immunotherapy; liver transplantation; transplant oncology.

Figure 1

The mechanism of action of immunosuppressants versus immune checkpoint inhibitors. The mechanism of action of checkpoint inhibitors is to prevent the “off” signal from being sent, allowing the T cells to kill cancer cells. Such drugs that act against the checkpoint proteins are called CTLA-4 inhibitors, PD-1 inhibitors, and PD-L1 inhibitors. While the mechanism of action of immunosuppressants is that they all function to prevent allograft rejection by preventing/inhibiting cell activation, cytokine production, differentiation, and/or proliferation. ICPI: Immune Checkpoint Inhibitors, PD-1: Programmed Death-1, IST: immunosuppressive therapy, APA, Antigen-presenting cell; CTLA-4, cytotoxic T-lymphocyte–associated antigen 4; PD-L1, Programmed death-ligand 1.

Figure 2

The expected timeline for using Immune checkpoint inhibitors in liver transplantation patients with HCC. (A) ICPI will free the immune system and active T-cell to attack and kill cancer cells. This state of the “hyperactive” immune system occurs in the absence of the allograft. Once ICPI is held, the immune system will “cool off” and return gradually to the normal body immune state at which a new liver transplant can be achieved safely.(B) ICPI can be used post-transplant to treat cancer recurrence or new second primary cancer. In this setting, the immune system will be activated in the presence of the graft, so the risk of graft rejection will be higher at around 30% than the general population.