Inhibitor Immunotherapy- An Overview

Introduction

Cancer is derived from the Greek word “Karkinos” and is characterized by abnormal and uncontrollable cell growth. Chemotherapy, surgery, and radiotherapy have been the standard treatment options. However, their drawbacks include low specificity toward cancer cells, cytotoxicity, and little improvement in survival rate. Novel treatment strategies such as inhibitor immunotherapy have improved patient prognosis and quality of life to a great extent.

What Is Inhibitor Immunotherapy?

The immune system employs killer T-cells to combat cancer cells. However, cancer cells lower the body’s immunity by acting against it. Hence, inhibitor immunotherapy uses specific immunotherapeutic agents against these cancer cells. A notable example is immune checkpoint inhibitors (ICIs).

What Is the Mechanism of Action of Immune Checkpoint Inhibitors?

During the body's normal functioning, the circulating killer T-cells can recognize cancer cells as non-self, leading to their killing. But, as cancer cells are the body’s mutated cells, they can evade the immune response by adhering to receptors expressed on the killer T-cells. Examples of the receptors are programmed cell death protein receptor (PD-1), programmed cell death ligand-1, and cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4). ICIs suppress this interaction by binding to these receptors, thereby blocking the ability of cancer cells to shut down the immune system.

How Are Immune Checkpoint Inhibitors Administered?

Immune checkpoint inhibitors are injected into the patient’s vein (intravenous). Each infusion takes around half to one hour. The administration has no pre-injection requirements about drinking water or fasting.

What Are the Few Examples of Immune Checkpoint Inhibitors?

Immune checkpoint inhibitors are used against a wide variety of cancers. A few FDA-approved ICIs are explained below.

1. Pembrolizumab: Pembrolizumab is an anti-PD-1 ICI. The drug is most commonly given via intravenous infusion over 30 minutes every three weeks. It is approved as a single agent or in combination with chemotherapy in the following cancers:

• Melanoma (A type of skin cancer).

• Lung Cancer (Small-cell and Non-small cell).

• Head and Neck Cancer.

• Hodgkin’s Lymphoma.

• Urothelial Cancer.

• Stomach Cancer.

• Cervical Cancer.

• Liver Cancer.

• Kidney Cancer.

• Uterine Cancer.

• Bladder Cancer.

• Mismatch Repair Defect (Mismatch is an error during DNA formation).

• Breast Cancer.

• Merkel Cell Cancer (an uncommon form of skin cancer).

2. Ipilimumab: Ipilimumab acts against CTLA-4. It is used as a single agent and in combination with Nivolumab in advanced stages of melanoma with promising results.

3. Nivolumab: Nivolumab is an anti-PD-1 ICI. It is used in metastatic melanoma, lung cancer, and metastatic kidney cancer. It is also combined with Ipilimumab for metastatic melanoma.

4. Atezolizumab: Atezolizumab is a PDL-1 inhibitor. It is used in the urinary tract and lung cancer as a single agent. Combination therapy with other ICIs has not been authorized.

PARP Inhibition and ICIs- Poly-ADP-ribose polymerase (PARP) is an enzyme for DNA repair in a normal human body. PARP inhibitors are a new category in immunotherapy. These make cancer cells incapable of repair, making them more susceptible to treatment. These have been approved as a single treatment option for metastatic breast cancer, prostate, and ovarian cancers. However, active clinical trials are going on for combination therapy with ICIs in the above-listed cancers. Also, PARP inhibitors have been tried as an adjunct to radiotherapy and chemotherapy.

What Are the Advantages of Immune Checkpoint Inhibitors?

Immune checkpoint inhibitors are useful in several cancers. They have gained immense popularity over the years for better efficacy and safety than chemotherapy. The following are the many advantages of ICIs:

• Increased specificity toward cancer cells.

• Fewer side effects than conventional treatments.

• Improved patient’s quality of life.

• Improved patient's overall survival rate.

• Lower relapse rates.

What Are the Disadvantages of Immune Checkpoint Inhibitors?

• Improper tumor response due to resistance.

• Take longer time to work with some patients.

• Disease progression before clinical improvement is seen in some patients.

• Low clinical success in children.

• Limited availability across various countries.

• High cost.

What Are the Notable Side Effects of Immune Checkpoint Inhibitors?

ICIs augment a patient’s immunity. Hence, immune cells can attack healthy cells, which results in untoward side effects.

• Stomach: Gastritis is common. Symptoms include nausea, vomiting, and constipation.

• Intestines: One of the ICIs’ most common side effects is immune-mediated colitis (colon inflammation). Patients might suffer from bloating, change in bowel habits, diarrhea, flatulence, abdominal pain, and blood or mucus in stools. These occur about one month after the onset of therapy. Hepatitis has been reported with fatigue, low-grade fever, and increased liver enzymes.

• Skin: The most common side effects involving skin are dryness, itching, and rash. Skin color also might change. The rash is more common in patients treated with Ipilimumab than Pembrolizumab and Nivolumab.

• Endocrine-Related: The most prominent side effects are the pituitary gland and thyroid gland inflammation. Pituitary gland inflammation is also called hypophysitis. Hypophysitis is higher when the ICIs are given in combinational therapy. Clinical features are dizziness, fatigue, severe headache, nausea, vomiting, double and blurred vision, and irritability. The other less common endocrine side effects are hypothyroidism and adrenal gland insufficiency. Symptoms of hypothyroidism are cold intolerance, fatigue, constipation, weight gain, and palpitations. Diabetes due to inflammation of the pancreas is also a side effect.

• Muscles: Muscle pain, twitching, and weakness are common.

• Lungs: Inflammation of the lung lining, also known as pneumonitis, is a less common side effect. The clinical symptoms are cough, shortness of breath, chest pain, blood in sputum, and fatigue.

How Are the Side Effects Caused by Immune Checkpoint Inhibitors Managed?

The oncologists should educate the concerned patients about the side effects of ICIs before initiating treatment, as they might be unexpected. Side effects are managed depending on their severity. However, patients require timely follow-ups to monitor them.

• Liver function tests should be obtained before and during each cycle of treatment.

• For mild diarrhea, dietary modifications are recommended. Loperamide, an anti-motility medication, is advised. Liver imaging should be considered. For severe diarrhea, discontinuation of the ICI and corticosteroid therapy should be initiated.

• Chest imaging is indicated for lung-related changes. In severe cases, oxygen therapy and corticosteroids are advised. In addition, symptom alleviation, such as shortness of breath, is important.

• Skin creams and lukewarm oatmeal baths are recommended for itching, dryness, and rash. Some examples of severe skin toxicity in patients are Stevens-Johnson syndrome, Sweet’s syndrome, and toxic epidermal necrolysis (TEN). Such patients require urgent hospitalization as these can be fatal if left untreated.

• Acute adrenal insufficiency is a deadly condition requiring prompt intervention. Therefore, serial laboratory investigations and pituitary gland imaging are advocated in concurrent hypophysitis.

• Thyroid function tests must be obtained before and during treatment. A temporary stop to the treatment and hormonal therapy are needed.

Conclusion

Over the years, the successful use of ICIs has given a ray of hope to cancer patients. However, it is the concerned oncologist’s responsibility to advise the patients regarding advantages, disadvantages, side effects, and their management. However, the side effects can be managed depending on their severity and periodic follow-up.