What is Immune Checkpoint Inhibition?

Immune checkpoints regulate the immune response.

Maybe the immune system brings to mind images of white blood cells chomping on bacteria, or antibodies attacking a foreign invader -- your body's defenses against bacteria and viruses that can make you sick. More and more, however, the immune system is becoming known for its ability to detect, seek and destroy cancer cells.

With such a powerful force as the the immune system, there needs to be a way of dialing things down a notch so that normal, healthy cells aren't attacked by mistake.

Fortunately, the immune system is designed with these safety checks in place. However, cancer cells, having arisen from cells that were once normal, can sometimes use these "loopholes" and safety checks to their advantage, to avoid immune detection. These loopholes are known scientifically as immune checkpoints, and drugs that take out the checkpoints are checkpoint inhibitors.

Immune Checkpoints

Just like critical processes in business and logistics, the decision to mount an immune response often requires multiple “sign-offs” and “approvals” before the wheels are set into motion -- and each department may or may not carry the same weight; and a single department does not necessarily dictate the decision.

As such, several complex safeguards help keep the immune system from overreacting to a foreign invader or mistaking a component of “self” for a dangerous invader -- and these safeguards can be used sneakily by cancer cells to avoid immune detection...

but they can also be leveraged by drug developers to uncloak cancer cells so that they are no longer “invisible” to the immune system.

This biologic business decision of mounting an immune response sometimes importantly involves coordination with “the department of cell death” – that is, the programmed death 1 (PD-1) pathway regulating inflammatory responses in tissues.

Checkpoint Inhibitors are Drugs to Help T-cells get Marching Orders

This PD-1 pathway has a "direct line" to the T-cells, or the immune soldiers that go out and kill cancer cells; however, it's far from a sure thing that T-cell soldiers will organize themselves, form a front, and begin to destroy the cancer cells. That's because other departments also have input on T-cells and their activities. Their are multiple sign-offs that have to occur before the soldiers get their marching orders.

One of the the things that determines whether the marching orders are given is the PD1 receptor, which serves kind of like a prominent general in the chain of command. Two "advisors" to this general that strongly advise against declaring war on cancer cells are PDL-1 and PDL-2. These anti-war advisors, PDL-1 and PDL-2, are actually molecules that bind to PD1 receptors on T-cells, and when they bind, they tell the T-cells to stand down, that they have no marching orders against the cancer.

Cancer Cells May Try to Mass-produce "Anti-war Advisors"

Sometimes cancer cells make lots of anti-war advisors, in their own self interest.

One or both of PD-L1 and PD-L2, on cells in the tissues, including cancer cells, can bind to PD1 receptors on T-cells and inhibit their function. Blocking this interaction between PD-1 on T-cells and its two players, which are out on the surface of other cells, can result in stronger activation of T-cells, and a series of events that results in a swift inflammatory response.

Treatments that Target PD-1 or PD-L1

Some cancer cells produce large amounts of PD-L1, which helps them escape immune attack.

Drug development researchers can make monoclonal antibody treatments that target either the PD-1 receptor (the general) or the PD-L1 ligand (the anti-war advisor) to boost the immune response against cancer cells, and they have been used in treating certain cancers.

At first, the success was seen with solid tumors, but now these targets are being explored for hematologic cancers, or blood cancers, as well, such as leukemia, lymphoma and myeloma. In classic Hodgkin lymphoma, there is increased PD-1 ligand (PD-L1/2) production in the cancer cells, so there is optimism about vulnerability of Hodgkin lymphoma to PD-1 blockade.

Since these therapies boost the immune system by removing some of its safety loopholes, there is concern that this could lead to injury to healthy cells and related side effects in some people. Adverse events that are commonly associated with PD-1–blocking antibodies include itchiness, rash, and diarrhea. Less often they can cause more serious problems in the lungs, intestines, liver, kidneys, hormone-making glands, or other organs.

Many other treatments that target either PD-1 or PD-L1 are now being tested in clinical trials as well, both alone and combined with other drugs.

Only a few of these treatments have received FDA approval for use in cancer thus far, but many others are now being studied in clinical trials.

Sources

Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 Blockade with Nivolumab in Relapsed or Refractory Hodgkin’s Lymphoma. N Engl J Med. 2015;372(4):311-319.

Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252-64.

Romano E, Romero P. The therapeutic promise of disrupting the PD-1/PD-L1 immune checkpoint in cancer: unleashing the CD8 T cell mediated anti-tumor activity results in significant, unprecedented clinical efficacy in various solid tumors. J Immunother Cancer. 2015;3:15.

American Cancer Society. Immune checkpoint inhibitors to treat cancer. Accessed December 2015.

 

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