Immune Checkpoint Blockade in Hepatocellular Carcinoma: 2017 Update
Authors: M Kudo
Journal: Liver Cancer (2016)

The immune checkpoint molecule programmed cell death 1 (PD-1) was discovered in 1992 by Professor Tasuku Honjo and his research team at Kyoto University [1]. They later discovered that PD-1 is involved in immunosuppression and is a receptor that acts as a “brake” for the immune response in knockout mice. In 2000, a joint research project between the Honjo group at Kyoto University and the Genetics Institute together with Harvard University discovered the ligands of PD-1 (PD-L1 and PD-L2) [2,3,4,5]. In 2002, Iwai et al. [6] found that enhancing immune activation by inhibiting the binding of PD-1 to its ligands in mouse models markedly enhanced antitumor activity. In 2005, Ono Pharmaceutical and the American company Medarex took note of these findings and developed nivolumab, a human anti-PD-1 antibody. That same year, the U.S. Food and Drug Administration (FDA) recognized nivolumab as an investigational new drug, thereby enabling clinical trials to be started in the United States. In 2009, Bristol-Myers Squibb and Ono Pharmaceutical (BMS/ONO) began joint clinical trials of nivolumab. The results of clinical trials in patients with melanoma led to the approval of an anti-PD-1 antibody for the treatment of melanoma in Japan in July 2014, before any other country in the world. Nivolumab has also been evaluated in a series of clinical trials for non-small cell lung cancer and renal cell carcinoma and has yielded favorable outcomes.

In 1995, Dr. James Allison of the University of Texas discovered that another molecule, called cytotoxic T-lymphocyte-associated antigen (CTLA-4) [7], serves as an indicator of immune cell suppression [7]. In 1996, his team showed that tumors disappeared in mice treated with an antibody that inhibits the function of CTLA-4 [8]. CTLA-4 is also an immune checkpoint molecule. Bristol-Myers developed an anti-CTLA-4 antibody called ipilimumab, which was approved for the treatment of melanoma in the United States in March 2011 and in Europe in July 2011 [9]. It was later approved in Japan in July 2015.

When cancer cells develop, antigen-presenting cells (APCs) recognize tumor-associated antigens (TAAs), triggering in the lymph nodes the activation of immature T cells that will become CD8-positive T cells (the priming phase). Once activated, the T cells travel throughout the bloodstream and reach the tumor site. There, they attempt to attack tumor cells by releasing molecules such as perforin and granzymes (the effector phase) (fig ​(fig1)1) [10]. Moreover, recognition of TAAs by T cell receptors (TCR) triggers the release of interferon gamma (IFN-γ) and other cytokines by CD8-positive T cells in an attempt to attack the cancer. However, tumor cells protect themselves by expressing IFN-γ induced PD-L1 or PD-L2, which binds to PD-1. When this happens, PD-1/PD-L1 binding attenuate the antitumor immune response, thereby weakening the attacking power of the T cells. This is called immune escape or immune tolerance (fig. ​(fig.2).2). The anti-PD-1 antibody blocks PD-1 on activated T cells from binding to PD-L1 or PD-L2 on APCs or tumor cells. This removes the “brake” on the immune system and restores the ability of T cells to attack tumor cells (fig. ​(fig.3).3). Unlike conventional chemotherapy or molecular targeted therapy, anti-PD-1 antibody achieves its antitumor effect by restoring the original potential of the natural human immune system as a powerful and precise weapon against cancer cells [11,12,13,14,15,16,17,18,19,20,21,22]. Antibodies against PD-L1 expression in the cancer tissue are believed to have a similar effect [23]. The recognition of “immuno-oncology” using immune checkpoint inhibitors was considered the “Breakthrough of the Year” by the American journal Science in 2013, and immuno-oncology has been widely publicized. PD-L1 also serves as a biomarker that predicts the response to anti-PD-1 antibody [24]. In addition, Kupffer-phase Sonazoid contrast-enhanced ultrasonography is an effective imaging method for predicting the response to treatment with anti-PD-1 antibody [25].






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Fig. 1


The cancer-immunity cycle. The generation of immunity to cancer is a cyclic process that leads to an accumulation of immune-stimulatory factors. This cycle can be divided into seven major steps, starting with the release of antigens from cancer cells and ending with the killing of cancer cells. CTLs=cytotoxic T lymphocytes. Reproduced with permission from Chen DS, et al. [10]