A basic guide to checkpoint inhibitors

This article is part of an ongoing series on new developments in cancer, including immunotherapies such as CAR T therapy And checkpoint inhibitors. Future installments will continue to demystify checkpoint inhibitors and explore the latest research expanding the field.

In March 2011, a new advancement in cancer came into the spotlight. This drug, known as a checkpoint inhibitor, stood out from chemotherapy and other standard cancer treatments. Rather than targeting cancer cells directly, this immunotherapy enhances the immune system’s innate ability to fight tumors. Initial clinical trials have shown that the therapy can improve overall survival and risk of death for patients with one of the deadliest forms of skin cancer, unresectable or metastatic melanoma.

Today, research into checkpoint inhibitors extends far beyond melanoma. Scientists are trying to discover more about the therapy, especially when it is given alongside other cancer treatments. Although the journey to understanding checkpoint inhibitors can be overwhelming, this article can guide you through the first steps. Subsequent articles will delve deeper into specific checkpoint inhibitors and other recent discoveries.

What are Checkpoint Inhibitors?

Checkpoint inhibitors (ICIs) are an antibody-based cancer drug. These infusions contain antibodies that target certain proteins called immune checkpoints.

Normally, the immune system relies on checkpoint proteins to disable overactive white blood T cells. This mechanism is essential for protecting the body and prevents irritable T cells from damaging healthy tissues. However, cancer cells use these checkpoints to their own advantage. By binding to these checkpoints, cancer cells shut down T cells that would otherwise turn against them, allowing them to multiply unchecked.

Inhibitor drugs loosen the biological constraints of these T cells. Most inhibitors are designed to bind to T-cell checkpoint proteins before a cancer cell can; some inhibitors instead bind to the checkpoint ligand on the cancer cell. Either way, these interactions prevent the cancer cell from silencing the T cell. T cells are then free to activate and eliminate the tumors.

What cancers do checkpoint inhibitors treat?

Checkpoint inhibitors were first approved for advanced skin cancer. Now these drugs can treat more than 25 types of solid tumors. The list includes:

• Bladder cancer
• Breast cancer
• Colon and rectal cancer
• Kidney cancer
• Liver cancer
• Non-small lung cell cancer
• Melanoma
• Pancreatic cancer

Checkpoint inhibitors can also treat Hodgkin’s and non-Hodgkin’s lymphoma, two types of blood cancer. However, the FDA has not approved them for treating other types of blood cancers, such as leukemia or myeloma, although this could change with ongoing research. Another recent immunotherapy, chimeric antigen receptor T-cell therapy (CAR T therapy), has shown promising results in this area. Table 1 provides a comprehensive list of cancers treated with specific checkpoint inhibitors.

When Should You Consider Checkpoint Inhibitors?

Checkpoint inhibitors are increasingly being given as a first treatment, especially for people with advanced melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (a type of kidney cancer) or Hodgkin’s lymphoma who are not eligible for a bone marrow transplant. For other diseases, including bladder cancer or head and neck cancer, checkpoint inhibitors are considered after other standard treatment options prove ineffective.

Inhibitors can also be administered before surgery or in addition to other cancer treatments, such as chemotherapy, radiation, and CAR T therapy. Combination treatments synergistically target tumors from different angles. For example, chemotherapy and radiation damage and kill cancer cells directly, while the inhibitor encourages immune cells to take revenge. Checkpoint inhibition may allow less invasive surgery or eliminate the need for surgery in some cases.

Ultimately, the decision to switch to checkpoint inhibitors will depend on each person’s basic health care, what treatment options they have tried, and the expected efficacy of checkpoint inhibitors for their disease.

How effective are checkpoint inhibitors?

Exactly how effective are checkpoint inhibitors in treating cancer? This can be a difficult question to answer. Checkpoint inhibitors do not cure; instead, they slow or reduce tumor progression to varying degrees. Its effectiveness is affected by several factors, including what treatments a person has already undergone and the type of cancer at hand. Results may also differ if the infusion is given with other checkpoint inhibitors or cancer treatments.

People with Hodgkin’s lymphoma, melanomaor solid tumors with specific genetic characteristics (Microsatellite Instability-High, MI-H) tend to respond more readily to checkpoint inhibitor therapy. In one clinical trial approx 87% of participants with Hodgkin’s lymphoma responded to nivolumab, a checkpoint inhibitor from Bristol Myers Squibb. In melanoma, inhibitors can approximately reduce tumor size 45-60% of patients with advanced melanoma, a significant improvement over historical response rates of less than 10%. A combination of two inhibitors with different checkpoint targets, CLTA-4 and PD-1may further improve outcomes, with overall five-year survival rates more than 50% in some studies.

The response rate for other solid tumors ranges from 15% to 30%. However, it is critical to note that many patients do not respond to checkpoint inhibitor therapy.

What does the procedure look like?

Checkpoint inhibitors are administered via an injection into the arm intravenous (IV) line. The number of infusions required varies depending on the specific inhibitor drug. They can be administered once or twice a month for up to a year or more.

A blood test is required before each session. These tests provide a baseline and reference point to monitor for any adverse effects during treatment. No other pre-treatment is necessary. The actual session lasts between 30 and 60 minutes. The medical staff will then monitor the patient for any adverse reactions.

What adverse effects can occur?

Checkpoint inhibitors trigger a wave of immune responses from the body. This mechanism is vital for attacking cancer, but can also encourage the immune system to attack normal, healthy cells. As a result, people taking checkpoint inhibitors may experience immune-related side effects.

Immune-related symptoms can manifest itself in various organs in the body. The skin may develop a rash, itching or loss of color. The colon, lungs and liver can become chronically inflamed. In rarer cases, inflammation can affect the brain. In a minority of patients, inhibitors may also cause the onset of diabetes or an exacerbation of pre-existing type II diabetes (less than 2%).

Doctors carefully monitor patients before and after each infusion. They may stop treatment temporarily and use corticosteroids or antibiotics to control symptoms.

Transplant recipients or those with underlying autoimmune diseases should carefully consider whether checkpoint inhibitors are appropriate for them. Because these inhibitors stimulate the immune system, treatment can worsen pre-existing conditions. Some studies suggest that symptoms are generally manageable, but each healthcare provider will make the final decision on a case-by-case basis.

Strikingly, these immune-related reactions are usually less toxic than those caused by chemotherapy and radiation, which target cancer cells directly; features of chemotherapy or radiation therapy, such as alopecia or a decreased blood cell count, are not typical. However, increased toxicity may also occur when checkpoint inhibitors are combined with these other treatments.

Takeaways

Checkpoint inhibitors represent a revolutionary advance in cancer care and offer a promising alternative to traditional treatments such as chemotherapy and radiation. These drugs have shown remarkable efficacy in unleashing the body’s immune system to target and destroy cancer cells, especially in the treatment of advanced melanoma and other solid tumors. But like any powerful tool, checkpoint inhibitors come with potential risks and complexities. Continuing this exploration of checkpoint inhibitors, future articles in this series will delve deeper into the complexities of combining them with other therapies and on ongoing research efforts to optimize their effectiveness. Stay tuned for further insights into this evolving frontier of cancer treatment.