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is ipilimumab a checkpoint inhibitor?

5 Answer(s) Available
Answer # 1 #

Checkpoint inhibitor therapy is a form of cancer immunotherapy. The therapy targets immune checkpoints, key regulators of the immune system that when stimulated can dampen the immune response to an immunologic stimulus. Some cancers can protect themselves from attack by stimulating immune checkpoint targets. Checkpoint therapy can block inhibitory checkpoints, restoring immune system function. The first anti-cancer drug targeting an immune checkpoint was ipilimumab, a CTLA4 blocker approved in the United States in 2011.

Currently approved checkpoint inhibitors target the molecules CTLA4, PD-1, and PD-L1. PD-1 is the transmembrane programmed cell death 1 protein (also called PDCD1 and CD279), which interacts with PD-L1 (PD-1 ligand 1, or CD274). PD-L1 on the cell surface binds to PD-1 on an immune cell surface, which inhibits immune cell activity. Among PD-L1 functions is a key regulatory role on T cell activities. It appears that (cancer-mediated) upregulation of PD-L1 on the cell surface may inhibit T cells that might otherwise attack. Antibodies that bind to either PD-1 or PD-L1 and therefore block the interaction may allow the T-cells to attack the tumor.

The discoveries in basic science allowing checkpoint inhibitor therapies led to James P. Allison and Tasuku Honjo winning the Tang Prize in Biopharmaceutical Science and the Nobel Prize in Physiology or Medicine in 2018.

The first checkpoint antibody approved by the FDA was ipilimumab, approved in 2011 for treatment of melanoma. It blocks the immune checkpoint molecule CTLA-4. Clinical trials have also shown some benefits of anti-CTLA-4 therapy on lung cancer or pancreatic cancer, specifically in combination with other drugs.

However, patients treated with check-point blockade (specifically CTLA-4 blocking antibodies), or a combination of check-point blocking antibodies, are at high risk of suffering from immune-related adverse events such as dermatologic, gastrointestinal, endocrine, or hepatic autoimmune reactions. These are most likely due to the breadth of the induced T-cell activation when anti-CTLA-4 antibodies are administered by injection in the blood stream.

Using a mouse model of bladder cancer, researchers have found that a local injection of a low dose anti-CTLA-4 in the tumour area had the same tumour inhibiting capacity as when the antibody was delivered in the blood. At the same time the levels of circulating antibodies were lower, suggesting that local administration of the anti-CTLA-4 therapy might result in fewer adverse events.

Initial clinical trial results with IgG4 PD-1 antibody nivolumab (under the brand name Opdivo and developed by Bristol-Myers Squibb) were published in 2010. It was approved in 2014. Nivolumab is approved to treat melanoma, lung cancer, kidney cancer, bladder cancer, head and neck cancer, and Hodgkin's lymphoma.

In May 2016, PD-L1 inhibitor atezolizumab was approved for treating bladder cancer.

Other modes of enhancing immunotherapy include targeting so-called intrinsic checkpoint blockades. Many of these intrinsic regulators include molecules with ubiquitin ligase activity, including CBLB, and CISH.

More recently, CISH (cytokine-inducible SH2-containing protein), another molecule with ubiquitin ligase activity, was found to be induced by T cell receptor ligation (TCR) and negatively regulate it by targeting the critical signaling intermediate PLC-gamma-1 for degradation. The deletion of CISH in effector T cells has been shown to dramatically augment TCR signaling and subsequent effector cytokine release, proliferation and survival. The adoptive transfer of tumor-specific effector T cells knocked out or knocked down for CISH resulted in a significant increase in functional avidity and long-term tumor immunity. Surprisingly there was no changes in activity of Cish's purported target, STAT5. CISH knock out in T cells increased PD-1 expression and the adoptive transfer of CISH knock out T cells synergistically combined with PD-1 antibody blockade resulting in durable tumor regression and survival in a preclinical animal model. Thus, Cish represents a new class of T-cell intrinsic immunologic checkpoints with the potential to radically enhance adoptive immunotherapies for cancer.

Immunological adverse effects may be caused by checkpoint inhibitors. Altering checkpoint inhibition can have diverse effects on most organ systems of the body. Colitis (inflammation of the colon) occurs commonly. The precise mechanism is unknown, but differs in some respects based on the molecule targeted. Infusion of checkpoint inhibitors has also been associated with acute seronegative myasthenia gravis. A lower incidence of hypothyroidism was observed in a trial of combined B cell depletion and immune checkpoint inhibitor treatment compared with studies of immune checkpoint inhibitor monotherapy. This holds promise for combining check point inhibitor therapy with immunosuppressive drugs to achieve anti-cancer effects with less toxicity.

Studies are beginning to show that intrinsic factors, such as species of the genus Bacteroides that inhabit the gut microbiome prospectively modify risk of developing immune related adverse events. Further evidence of this can be found in patients that saw reversal of immune toxicity following fecal microbiome transplant from healthy donors.

Cody Cutrono
Answer # 2 #

Checkpoint inhibitors are a type of immunotherapy. They are a treatment for cancers such as melanoma skin cancer and lung cancer.

These drugs block different checkpoint proteins. You might also hear them named after these checkpoint proteins – for example, CTLA-4 inhibitors, PD-1 inhibitors and PD-L1 inhibitors.

Examples of checkpoint inhibitors include pembrolizumab (Keytruda), ipilimumab (Yervoy), nivolumab (Opdivo) and atezolizumab (Tecentriq).

Checkpoint inhibitors are a type of immunotherapy. They block proteins that stop the immune system from attacking the cancer cells.

Cancer drugs do not always fit easily into a certain type of treatment. This is because some drugs work in more than one way and belong to more than one group.

Checkpoint inhibitors are also described as a type of monoclonal antibody or targeted treatment.

Our immune system protects us from disease, killing bacteria and viruses. One main type of immune cell that does this is called a T cell.

T cells have proteins on them that turn on an immune response and other proteins that turn it off. These are called checkpoint proteins.

Some checkpoint proteins help tell T cells to become active, for example when an infection is present. But if T cells are active for too long, or react to things they shouldn’t, they can start to destroy healthy cells and tissues. So other checkpoints help tell T cells to switch off.

Some cancer cells make high levels of proteins. These can switch off T cells, when they should really be attacking the cancer cells. So the cancer cells are pushing a stop button on the immune system. And the T cells can no longer recognise and kill cancer cells.

Drugs that block checkpoint proteins are called checkpoint inhibitors. They stop the proteins on the cancer cells from pushing the stop button. This turns the immune system back on and the T cells are able to find and attack the cancer cells.

These drugs block different checkpoint proteins including:

CTLA-4 and PD-1 are found on T cells. PD-L1 are on cancer cells.

Checkpoint inhibitors that block PD-1 include:

Nivolumab and pembrolizumab are treatments for some people with:

Nivolumab is also a treatment for some kidney cancers and head and neck cancers. And pembrolizumab is used for cancers of the urinary tract.

The urinary tract includes the:

Ipilimumab (Yervoy) is a checkpoint inhibitor drug that blocks CTLA-4. It is a treatment for advanced melanoma and advanced renal cell cancer.

Checkpoint inhibitors that block PD-L1 include:

Atezolizumab is a treatment for:

The urinary tract includes the:

Avelumab is a treatment for a type of skin cancer called merkel cell carcinoma (MCC) that has spread to other parts of the body. It is also a treatment for some cancers of the urinary tract (urothelial cancers).

Durvalumab is a treatment for non small cell lung cancer (NSCLC).

Ask your doctor if these drugs are suitable for you. Whether you can have this treatment depends on your type of cancer. It might also depend on:

To find out if you can have pembrolizumab for non small cell lung cancer, you need to have your cancer cells tested. To have this PD-1 inhibitor for lung cancer, you need to have large amounts of the PD-L1 protein on your cancer cells. This is called PL-L1 positive cancer.

This testing does not apply to all checkpoint inhibitors. Your doctor or specialist nurse can tell you if this applies to you.

You might be offered checkpoint inhibitors as part of a clinical trial. Or you could ask your doctor whether there are any trials that you could take part in.

You usually have these drugs as a treatment through a drip into your bloodstream.

These drugs boost all the immune cells, not just the ones that target cancer. So the overactive T cells can cause possible side effects. These might include:

These drugs can also disrupt the normal working of the liver, kidneys and hormone making glands (such as the thyroid). You have regular blood tests to check for this.

Some of these side effects can be serious. Your medical team will talk through the possible side effects so you know what to look out for. Tell your doctor or nurse if you have any side effects so they can treat them as soon as possible.

Side effects, such as diarrhoea, can be serious. You are also likely to have worse side effects if you have ipilimumab and nivolumab together. You might have these 2 drugs if you have advanced melanoma or advanced renal cell cancer.

Datta Datt
Answer # 3 #

This therapy is sometimes called immune checkpoint blockade because the molecule that acts as a brake on immune cells — the checkpoint — is blocked by the drug.

Our researchers have played a leading role in developing checkpoint inhibitors and demonstrating their safety and effectiveness in cancer patients.

MSK has helped lead several clinical trials showing that checkpoint inhibitors can be effective against melanoma and lung cancer, and these drugs are being tested at MSK against sarcoma, lymphoma, and several other cancers.

One drug called ipilimumab (Yervoy®) blocks a checkpoint protein called CTLA-4. Two additional drugs, pembrolizumab (Keytruda®) and nivolumab (Opdivo®), target another checkpoint protein called PD-1. A third drug, atezolizumab (Tecentriq®), targets one called PD-L1.These drugs all became available within the last few years. The US Food and Drug Administration (FDA) approved ipilimumab in 2011 and pembrolizumab and nivolumab in 2014, all for the treatment of melanoma. In 2015, the FDA also approved nivolumab and pembrolizumab for non-small cell lung cancer, and nivolumab for renal cell carcinoma.

Several additional checkpoint drugs are being studied and investigated in clinical trials at MSK.

Apoorva Bharathiraja
Answer # 4 #

An important part of the immune system is its ability to tell between normal cells in the body and those it sees as “foreign” (such as germs and cancer cells). This allows the immune system to attack the foreign cells while leaving normal cells alone.

Part of how the immune system does this is by using “checkpoint” proteins on immune cells. The checkpoints act like switches that need to be turned on (or off) to start an immune response. But cancer cells sometimes find ways to use these checkpoints to avoid being attacked by the immune system.

Medicines known as monoclonal antibodies can be designed to target these checkpoint proteins.  These drugs are called immune checkpoint inhibitors (or just checkpoint inhibitors).

Checkpoint inhibitors don't kill cancer cells directly. They work by helping the immune system to better find and attack the cancer cells, wherever they are in the body.

Medicines that target different checkpoint proteins are now used to treat some types of cancer. All of these drugs are given as an infusion into a vein (IV).

PD-1 is a checkpoint protein on immune cells called T cells. It normally acts as a type of “off switch” that helps keep the T cells from attacking other cells in the body. It does this when it attaches to PD-L1, a protein on some normal (and cancer) cells. When PD-1 binds to PD-L1, it basically tells the T cell to leave the other cell alone. Some cancer cells have large amounts of PD-L1, which helps them hide from an immune attack.

Monoclonal antibodies that target either PD-1 or PD-L1 can block this binding and boost the immune response against cancer cells.

Examples of drugs that target PD-1 include:

Examples of drugs that target PD-L1 include:

Both PD-1 and PD-L1 inhibitors have been shown to be helpful in treating many different types of cancer.

CTLA-4 is another checkpoint protein on some T cells that acts as a type of “off switch” to help keep the immune system in check.

Ipilimumab (Yervoy) and tremelimumab (Imjuno) are monoclonal antibodies that attach to CTLA-4 and stop it from working. This can help boost the body’s immune response against cancer cells.

These drugs are typically used along with a PD-1 or PD-L1 inhibitor. These combinations can be used to treat several types of cancer.

LAG-3 is a checkpoint protein on some types of immune cells that normally acts as a type of “off switch” to help keep the immune system in check.

Relatlimab is a monoclonal antibody that attaches to LAG-3 and stops it from working. This can help boost the body’s immune response against cancer cells.

This drug is given along with the PD-1 inhibitor nivolumab (in a combination known as Opdualag). It can be used to treat melanoma of the skin, and it’s being studied for use in several other types of cancer.

Some of the more common side effects of checkpoint inhibitors include:

Other, more serious side effects occur less often:

Bobbi Giordani
Chief Process Officer
Answer # 5 #

Currently, nivolumab and ipilimumab are the most widely used immune checkpoint inhibitors.

Blythe Considine