Explaining checkpoint inhibitors in cancer immunotherapy

Checkpoint inhibitors are one class of potent drugs currently in clinical trials for use in cancer immunotherapy approaches for cancer treatment. But, their mode of operation and underlying concept is more difficult to understand compared to other classes of immunotherapy for cancer such as chimeric antigen receptor engineered T cells (CART).


Specifically, checkpoint inhibitors are usually antibodies that bind to inhibitory receptors on the surface of T cells, whose typical roles include the identification of cancerous cells or foreign microbes such as viruses and bacteria, and mediating their subsequent destruction. In doing so, the checkpoint inhibitors release a brake on the immune system that prevent T cells from attacking cancer cells. Thus, what is a checkpoint and how does a cancer cell fool the immune system?


Cancer cells express surface molecules on their plasma membrane known as ligands, that bind to specific inhibitory receptors on T cells such as PD-1 and CTLA-4. Upon binding, the nefarious signals on the cancer cells (i.e., ligands) misled the T cell into thinking that the cancer cell is a normal healthy body cell. Hence, the T cell remain silent in attacking the cancer cells bound to it through the ligand-inhibitory receptor pair.


Thus, what does checkpoint inhibitors do to ameliorate the situation? Specifically, checkpoint inhibitors are antibodies that bind to the inhibitory receptors on T cells; thereby, preventing them from binding ligands on the cancer cell and the formation of a checkpoint. Without the ability to bind to ligands on cancer cells, T cells are essentially deaf to the signals presented, and thus, regain the ability to mount an attack on the cancer cells. This is known as the concept of releasing the brake on the immune system for attacking cancer cells. Without the brake, many tumours in patients have been reported to shrink substantially, sometimes in as quickly as a few days.


However, releasing the brake on the immune system does raise safety concerns such as the misidentification of healthy body cells as foreign ones by immune cells; thus, resulting in autoimmune attacks on organs and tissues that may result in death. In particular, there have been reports, over the years, about patients taking cancer immunotherapy drugs (last resort treatment) that eventually succumb to the side effects of multiple organ failure. This occurs after the patients are in remission, where almost all cancer cells in the body have been wiped out by immunotherapy drugs.


Thus, improving the side effects profile of immunotherapy drugs and tuning the strength of the immune response elicited against cancer are avenues in which cancer researchers are exploring to enhance the safety and efficacy of cancer immunotherapy treatment.


Category: cancer, drug discovery,

Tags: cancer immunotherapy, checkpoint inhibitors, antibodies, cell surface markers, drug discovery,


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