Immunotherapy-Related Adverse Events - An Overview

Introduction:

Immunotherapy has reformed cancer treatment by utilizing the immune system to fight cancer cells. It has shown successful outcomes and increased survival rates. However, it can lead to side effects, known as immunotherapy-related adverse events (irAEs), which require prompt treatment and careful monitoring. This article provides an overview of immunotherapy-related adverse events and their management strategies.

What Is Immunotherapy?

Immunotherapy is a type of cancer treatment that makes use of the body's immune system to recognize and fight cancer cells. The immune system, comprised of tissues, cells, and organs, plays a crucial role in defending the body against invaders, including bacteria, viruses, and cancer cells. The various types of immunotherapy approaches include:

• Immune Checkpoint Inhibitors: These drugs block the specific proteins present in immune cells or cancer cells called checkpoints. This, in turn, causes the immune system to attack the cancer cells. The two most well-known immune checkpoint proteins are cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1).

• Monoclonal Antibodies: These antibodies, produced in the laboratory, specifically recognize and target proteins in cancer cells, leading to their destruction.

• Adoptive Cell Transfer: It is a type of immunotherapy in which immune cells, particularly T-cells, are collected from the patient's blood. These cells are then enhanced in the laboratory and subsequently reinfused back into the patient's body.

• Cancer Vaccines: These vaccines stimulate the immune system to recognize and combat cancer cells. Different types of cancer vaccines include peptide vaccines, which contain small protein fragments with cancer-associated antigens, and dendritic cell vaccines, where dendritic cells are extracted from the patient, loaded with cancer-related antigens, and reintroduced into the body.

• Cytokines: These proteins are naturally occurring and play a crucial role in regulating the immune system, enhancing its activity.

What Are Immunotherapy-Related Adverse Events?

Immunotherapy-related adverse events are the complications that occur due to immunotherapy treatment. The severity of these complications varies among individuals, and not all patients will experience these adverse events. Some common events include:

1. Skin Reactions: This is one of the most commonly observed irAEs, and its typical symptoms include itching, rashes, blistering, dryness, pruritus, vitiligo, and changes in skin color. Rashes often occur on the extremities and trunk. In severe cases, Stevens-Johnson syndrome or toxic epidermal necrolysis may occur, characterized by extensive skin peeling in sheets along with blistering rashes.

2. Joints: The symptoms include swelling, erythema, warmth, and joint pain. The damage to the joints can progress quickly. In delayed cases, joint deformities can occur, which can limit movement.

3. Gastrointestinal IrAEs: The most common symptoms include diarrhea, nausea, vomiting, dysphagia (difficulty in swallowing), colitis which causes inflammation of the colon, abdominal pain, and loss of appetite. In severe cases, it can also cause bowel perforation, hematochezia (blood in the stools), or severe infections.

4. Hepatitis: It is the inflammation of the liver, and the patient may experience fatigue, jaundice (yellowing of the skin or sclera), and pain in the abdomen, and is also associated with elevated liver enzymes.

5. Pneumonitis: It refers to the inflammation of the lungs, and the patient may experience shortness of breath, chest pain, cough, and flu-like symptoms. In severe cases, it may lead to respiratory failure.

6. Endocrine-Related IrAEs: It is a common type of adverse event that can present as hypothyroidism (reduced production of thyroid hormones), hyperthyroidism (increased production of thyroid hormones), adrenal insufficiency, diabetes mellitus (elevated blood glucose levels), hypophysitis (inflammation of the pituitary gland), or other hormonal imbalances. Endocrine toxicity can be challenging to identify due to nonspecific symptoms such as nausea, vomiting, weight loss, fatigue, low blood pressure, weakness, and headaches. If left unrecognized, it can lead to adrenal crisis, thyroid storm, severe hypocalcemia, or diabetic ketoacidosis.

7. Neurological IrAEs: Symptoms that can occur are peripheral neuropathy which causes tingling, or numbness in the extremities, headache, confusion, dizziness, and muscle weakness. In severe cases, it may cause inflammatory responses such as encephalitis (brain inflammation), myelitis (inflamed spinal cord), vasculitis (inflamed blood vessels), and meningitis (inflamed outer membranes of spinal cord and brain), and peripheral neuromuscular autoimmune disorders such as myasthenia gravis (an autoimmune disorder that causes weak skeletal muscles) and Guillain-Barre syndrome (a disorder that affects nerves).

8. Cardiac IrAEs: These complications occur less commonly. But can lead to myocarditis (inflammation of the heart muscle), pericarditis (inflammation of the membrane around the heart), or arrhythmias (abnormal heart rate).

9. Renal IrAEs: Kidney-related problems that can occur are renal dysfunction, electrolyte imbalances, or nephritis (inflammation of the kidneys). Acute interstitial nephritis (AIN), which is a type of kidney injury, is one of the common nephrotoxicity.

10. Hematological IrAEs: These complications include anemia, thrombocytopenia (low platelet count), or neutropenia (low white blood cell count).

11. Ocular IrAEs: These are very rare and can cause symptoms such as anterior uveitis (inflammation of the front part of the eye) or pan-uveitis (generalized inflammation of the eye). These complications occur in the treatment of melanoma which is a form of skin cancer.

What Are the Treatment Strategies for Immunotherapy-Related Adverse Events?

The treatment strategies include:

• In the case of gastrointestinal adverse events, systemic steroids such as oral Prednisolone can be administered, and if patients do not respond to steroids, Infliximab may be used. Conservative treatment options include using antidiarrheal agents, electrolyte replacement, and ensuring proper hydration.

• For immune-mediated hepatitis, systemic steroids are typically prescribed. If patients do not respond to steroids, medications like Azathioprine or Tacrolimus may be considered.

• In cases of immune-related nephrotoxicity, basic therapy involves the use of systemic steroids.

• Endocrine toxicity is managed by replacing deficient hormones, and hormone levels should be monitored closely.

• In hematologic toxicities, systemic steroids are often considered, and supportive care may involve transfusions.

• Joint inflammations can be treated with steroids, intra-articular steroid injections, and non-steroidal anti-inflammatory drugs (NSAIDs).

• Skin complications can be managed with topical corticosteroids or antihistamines. Gabapentin can be used for severe pruritus.

• In cases of pneumonitis, systemic steroids and immunosuppressive medications are typically considered.

Conclusion:

Immunotherapy can lead to various side effects affecting the entire body. Early detection and prompt treatment of these adverse events can contribute to improved outcomes. The primary treatment for irAEs often involves the use of systemic steroids, followed by supportive care.