A deeper look at anti-PD-1/PD-L1 checkpoint inhibitors for cancer

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In an earlier story I described pembrolizumab, a PD-1 targeting checkpoint inhibitor, in some detail. Since its launch, several companies have introduced antibodies that target the same receptor. This article summarizes some of these recent developments and how they work.

Fight cancer with Checkpoint inhibitors

When many cancers expand, spread and recur, checkpoint inhibitors can help keep difficult tumors at bay. These antibody-based immunotherapies can restore the body’s ability to recognize and eliminate cancer cells – an approach that often plays well with other treatment options, including surgery, chemotherapy and radiation.

The antibodies are administered intravenously. Once in the blood, these antibodies block molecules called checkpoint proteins on immune T cells. This blocking interaction restores the immune system’s ability to recognize and kill cancer cells.

While not all inhibitors are the same, they are roughly the same half of the inhibitors currently on the market share the same immune target: a protein known as PD-1, which is found on T cells in white blood cells. This strategy demonstrates clinical efficacy for many cancers, including melanoma, lung and head and neck cancer.

What immune checkpoints do

Immune checkpoints are at the heart of this mechanism. This naturally occurring system helps the immune system maintain self-tolerance (the body’s ability to recognize itself against abnormal proteins resulting from cancer or infections) and minimize damage to healthy tissues from the immune response.

One important immune checkpoint is known as PD-1, or Programmed Cell Death Protein-1. This receptor is found on the surface of T cells and other immune cells. These proteins protect the body against strong immune reactions and autoimmunity. When PD-1 binds to its partner receptors on other cells, PD-L1 or PD-L2, it sends a signal to the T cell to paralyze its normal immune function.

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Block PD-1 checkpoints, shrink tumors

The immune system is equipped to suppress tumors on a small scale. Cancer cells overcome this antitumor activity by producing molecules that inhibit the killing of immune cells. By overexpressing PD-L1 checkpoint proteins, cancer cells can disable T cells that would otherwise attack the tumor.

Enter anti-PD-1 checkpoint inhibitors. These therapies bind antibodies against PD-1 proteins, preventing the PD-1 protein from binding to its ligands, PD-L1 or PD-L2. The resulting T cell is freed from its constraints and can maintain its activity in the tumor microenvironment. In an earlier story I described pembrolizumab, a PD-1 targeting checkpoint inhibitor, in some detail. Since its launch, several companies have introduced antibodies that target the same receptor. This article summarizes what they are and how they work.

Anti-PD-1 Checkpoint Inhibitors

Checkpoint inhibitors use antibodies to bind to and prevent checkpoint protein interactions. Currently, there are six federally approved checkpoint inhibitors that block PD-1 checkpoint receptors. Each inhibitor benefits a specific set of cancer types. For example, pembrolizumab, sold by Merck & Co., is indicated for the treatment of more than 18 different types of cancer. By comparison, BeiGene’s tislelizumab only won FDA approval for the treatment of patients with a certain type of esophageal cancer.

These drugs can be administered alone as monotherapy or together with other cancer treatments, including inhibitors that target different checkpoint proteins and chemotherapy. The characteristics of the cancer in question will determine how each inhibitor is used.

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Side effects

Although successful in treating several cancers, anti-PD-1 therapies can trigger several side effects. Most reactions occur as a result of unleashing immune activity, resulting in a variety of problems. Most notably, the inhibitors can cause inflammation throughout the body, such as on the skin or in the lungs, colon, or liver. These inhibitors can also disrupt hormone levels in the thyroid and adrenal glands.

The skin may itch or become red with a rash. Problems with pneumonia, or pneumoniaoften cause coughing, shortness of breath and fever. Patients with colitis typically experience frequent diarrhea, abdominal pain, nausea, vomiting, fatigue, or loss of appetite. Liver and kidney disorders can similarly cause nausea, fatigue, or loss of appetite. Patients also often report pain in the joints, back and/or muscles.

Although these side effects can range from mild to life-threatening, checkpoint inhibitors are generally considered more tolerable than chemotherapy and radiation. Doctors monitor each patient to prevent these reactions from becoming life-threatening and are often successful.

Targets partner receptors PD-L1 and PD-L2

Originally, checkpoint inhibitors could only target T cells to interfere with the PD-1 immune checkpoint axis. It is now possible to interrupt PD-1 interactions by targeting PD-1’s partner receptors on other cells.

PD-1 possesses two known binding partners: PD-L1 and PD-L2. These proteins are often overexpressed on tumor cells. Although federally approved checkpoint inhibitors for the former exist, the clinical potential for the latter is still under investigation.

There are three anti-PD-L1 inhibitors available for use: atezolizumab (Tecentriq), durvalumab (Imfinzi), and avelumab (Bavencio). They emerged a few years after the FDA approved the first anti-PD-1 inhibitor.

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Interestingly, although these inhibitors target the opposite side of the PD-1 axis, they do not treat exactly the same diseases as their anti-PD-1 counterparts. Certain types of cancer, such as a type of soft tissue tumor alveolar sarcoma of the soft part And small cell lung cancer, have shown improvement only under anti-PD-L1 inhibitors. For other cancers, including non-small cell lung cancer, hepatocellular carcinoma and melanoma, either type of inhibitor could provide clinical benefit. The decision between which inhibitor to choose will depend on several factors, such as the available efficacy data for the disease and the patient’s previous treatment history.

Potential future research

The full potential of anti-PD-1 checkpoint inhibitors remains untapped. Investigational inhibitors will continue to gain approval and continue to expand the applicability of this inhibition mechanism. However, there is an important caveat. Although these drugs can help suppress difficult-to-treat tumors, their effect is not consistent across different types of cancer; some tumors respond better than others. As a result, improving drug safety profiles and overall clinical benefit are important research focuses for the field.

Clinical trials administering anti-PD-1 inhibitors alongside other established cancer treatments, such as chemotherapy, are critical to understanding how best to implement this therapy. Although combining clearly targeted inhibitors is possible, one anti-PD-1 and anti-PD-L1 The inhibitor regimen has yet to be approved. With more research, anti-PD-L1 and anti-PD-L2 targeted therapies could one day join this pool.

Takeaways

Checkpoint inhibitors represent one of the most important developments in cancer treatment over the past two decades. While they are not the answer to all cancers, their impact is profound, especially when used in combination with other treatments such as therapy, chemotherapy and emerging cell-based therapies such as CAR T therapy. This is just the beginning; As research continues and new checkpoints are discovered, the potential of these therapies will only increase, offering more hope for cancer patients.


This article joins a growing series on monocancer treatments, including new immunotherapies such as CAR T therapy And checkpoint inhibitors. Find more at www.williamhaseltine.com.

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