Checkpoint Inhibitors for Cancer Treatment

One of the major issues preventing effective treatment of many cancers concerns the reduced ability of the body to defend itself against attack as some cancer cells have the capacity to deactivate the T lymphocytes (T cells) of the immune system.

Under normal circumstances, T cells are not triggered to attack healthy cells because healthy human cells carry a protein known as Programmed death-ligand 1 (PD-L1). When a the checkpoint protein programmed cell death protein 1 (PD-1) on the T cell can bind to the PD-L1 of a normal cell, the immune system recognizes the normal cell as being non-pathogenic. Yet some cancer cells also carry large amounts of PD-L1 and so evade attack from the immune system simply because the cells are not recognized as malignant.

Immune checkpoint blockers are monoclonal antibodies which disable either the PD-1 of the T cell or the PD-L1 protein on other cells preventing the binding from taking place.  This leaves the immune system free to attack the malignant cell.

Another protein which normally resides in healthy cells but which can also be carried by certain cancer cells is cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Ipilimumab has been developed to prevent this protein from binding to immune cells.

Immune checkpoint inhibitors are an important advance in cancer treatments, and there are several drugs currently available which target either the PD-1 checkpoints or the PD-L1 proteins. The most commonly used are:

PD-1

Cemiplimab (Libtayo)

Pembrolizumab (Keytruda)

Nivolumab (Opdivo)

Cemiplimab-rwlc (Libtayo)

PD-L1

Atezolizumab (Tecentriq)

Avelumab (Bavencio)

Durvalumab (Imfinzi)

CTLA-4

Ipilimumab (Yervoy)

Currently, these treatments are generally employed only against cancers which are known to carry the PD-L1 and CTLA-4 binding proteins, namely advanced melanoma, which is unresectable or metastatic, and non-small cell lung cancer.   The medicines have found some success on these cancers.. Trials are also underway to find out if they work on other types of cancers.  Combinations are also a possibility and one trial showed melanoma patients treated with nivolumab and ipilimumab had good results.  Pembrolizumab is projected to be the number 1 top-selling drug in the world (by retail sales) by 2024.  It is already one of the top selling cancer drugs in the US with 2018 sales of $4.18 billion.

These immunotherapy treatments essentially prevent protein binding not only to pathogenic cells but also to healthy ones, which can cause side effects.  Sometimes the checkpoint inhibitors become a double-edged sword as the T-cells attack and disrupt the normal function of healthy organs and tissues.

Unfortunately, it is difficult to predict how frequently and severe such issues will be. Although few deaths have been recorded as arising directly from the toxicity of these drugs, some investigators feel there is evidence that fatalities from severe side-effects occur. The manufacturers of the checkpoint inhibitors warn clinicians and patients that there is a risk of a positive feedback loop forming in the immune system, causing the immune system to attack healthy organs leading to severe problems.  Doctors need to be careful when giving these drugs to patients with autoimmune disease. There is also some concern that when patients take antibiotics in advance of cancer treatment, the effectiveness of checkpoint inhibitors could be reduced. Experts are calling for more research on this issue.

See also: http://jamanetwork.com/journals/jamaoncology/fullarticle/2174768

Dana-Farber Cancer Center made this video about checkpoint inhibitors:

The 2018 Nobel Prize for physiology or medicine was awarded to James Allison and Tasuku Honjo for their work with checkpoint inhibitors.