Immunotherapy

Immunotherapy, also known as biological therapy, is a type of clinical treatment that either activates (activation immunotherapy) the patient’s immune system or suppresses it (suppression immunotherapy) in order to control a disease and its progression. While in diseases like cancer, where the body’s immune system is failing, activation immunotherapy is needed to fight cancer growth, in pro-inflammatory conditions like allergies and autoimmune diseases, suppressing the hyperactive immunity with suppression immunotherapy is the main aim. Immunotherapy can be administered with immunomodulatory drugs (drugs that modulate the immune system response), vaccines (part of cancer therapy) or desensitisation against allergens like peanuts with oral immunotherapy (OIT).

Broadly, two types of immunotherapy exist – suppression immunotherapy and activation immunotherapy.

Suppression immunotherapy: Pro-inflammatory and other states of exaggerated immune response are brought under control with suppression immunotherapy. Additionally, the normal immune response can also be reduced in cases of organ transplants to prevent rejection. The conditions in which this type of immunotherapy is used include:

• Autoimmune diseases, like rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) etc.
• Inflammatory bowel disease (IBD, Crohn’s disease and ulcerative colitis)
• Allergies, like a peanut allergy, etc.
• After organ transplantation surgeries to prevent graft rejection and failure of the organ

(Read more: Food allergies)

Common immunosuppressant drugs include:

• Corticosteroids: dexamethasone, prednisolone, budesonide, etc.
• Calcineurin inhibitors: cyclosporine, tacrolimus, etc.
• Biologicals: etanercept, adalimumab, infliximab, rituximab, etc.
• IMDH inhibitors: azathioprine, leflunomide, mycophenolate, etc.

Activation immunotherapy (or cancer immunotherapy): While traditionally cancer treatment focuses on killing off cancer cells or removing tumours surgically, recent advances in activation immunotherapy have made it possible to activate and revitalise the body’s waning immune system to fight off cancer cells. Various methods have been developed to activate and employ the body’s immune system to target cancer cells. Some used in clinical practice include:

• Immune checkpoint inhibitors: The naturally occurring checkpoints in the immune system prevents it from producing an exaggerated immune response or being hyperactive. Certain drugs have been created to block these immune checkpoint inhibitors and potentiate the immune system to respond more strongly to cancer cells. Examples of these drugs are Pembrolizumab (Keytruda) and Nivolumab (Opdivo).
• Monoclonal antibodies: The naturally occurring antibodies in the body bind with the antigen (molecules on the invading foreign cells) and bring about an immune attack geared towards it. In the case of cancer, tumour cells have genetic modifications that allow them to escape binding with the immune system’s antibodies. Monoclonal antibodies are molecules that are created in the laboratory and are administered as immunotherapy drugs in cancer. They seek and bind with tumour cells but they themselves appear as foreign antigens to the body’s own antibodies, thus allowing the immune system to attack the monoclonal antibody bound cancer cells. Some monoclonal antibodies even have chemotherapy medicines attached and help kill cancer cells. Examples of monoclonal antibodies that are used in cancer immunotherapy include rituximab, a monoclonal antibody that binds to CD20 receptors of B-cells and some cancer cells that is used in leukaemias and lymphomas.
• Adoptive T-cell transfer: Scientists remove some part of the tumorous growth and find and isolate the T-cells within it that are acting against it. Then they genetically engineer the genes in those T-cells to make them even stronger and reintroduce them into the patient intravenously. Examples of this type of therapy include CAR T-Cell therapy, used for acute leukaemia in children, where the T-cells are modified to express chimeric antigen receptors (CAR).
• Immunomodulators: These drugs modulate the immune response of the body. While immunosuppressive drugs are used in conditions like autoimmune diseases, allergies and after organ transplants, drugs that upregulate the immune system response are used in cancer. Besides immune checkpoint inhibitors, this category of immunotherapy agents include cytokines, interleukins and interferons. These drugs help further enhance the patient’s immune system response to cancer cells.
• Cancer vaccines: Certain cancers that are caused by viruses or progress from viral infections (hepatitis B can lead to liver cancer) can be prevented by vaccines. For example, human papillomavirus infection, which can lead to cancers of the cervix, oral cavity, anus and penis, can be prevented by the HPV vaccine. Additionally, the BCG vaccine that is used for tuberculosis prevention has been used to enhance the immune response in bladder cancer. Cancer treatment vaccines are being developed that target different aspects of immunity and award immune system responsiveness towards specific cancers. Sipuleucel is a cancer treatment vaccine used in prostate cancer.
• Oncolytic viruses: An oncolytic (cancer destroying) virus is one that preferentially infects cancer cells in the tumour mass and causes its destruction. It produces more viral particles, proliferates and further leads to complete destruction of the tumour. The first oncolytic virus therapy approved for clinical use was talimogene (V-TEC) and is used in melanoma (skin cancer) treatment.

As part of the normal function of the immune system, the body’s immune response mediating cells attack all foreign and abnormal cells. The same happens when a tumorous growth forms. Cancer cells are identified as alien by the body’s antigen-presenting cells and other immune cells are recruited to attack. These cells are often found in and around cancer cells in patients and are called tumour infiltrating lymphocytes (TILs). Those patients who have more tumour infiltrating lymphocytes (TILs) in their tumours indicate a stronger immune response against the cancer and have a better prognosis. However, the cancer cells have genetic modifications that allow them to escape identification by the patient’s immune system or can even turn the immune cells off. Thus, external aid is required to revitalise and activate the immune system to act against the cancer more effectively.

Activation immunotherapy has been found to be of therapeutic benefit in various cancers. Some examples include:

• Bladder cancer
• Brain cancer
• Breast cancer
• Cervical cancer and ovarian cancer
• Colorectal cancer
• Head and neck cancer
• Kidney cancer
• Liver cancer
• Lung cancer
• Leukaemia
• Prostate cancer
• Skin cancer
• Lymphoma

Immunotherapy drugs can be administered through various routes including:

• Intravenous (IV): Where cancer immunotherapy medicine goes directly into a vein.
• Oral: Where cancer immunotherapy drugs come in pills or capsules that are swallowed.
• Topical: Where cancer immunotherapy medicine formulation can come in a cream form that is rubbed onto the skin. An example of this mode of immunotherapy is the formulations used for very early skin cancer.
• Intravesical: Where cancer immunotherapy agent is introduced directly into the bladder in bladder cancer.

Following are some of the benefits of activation immunotherapy for cancer treatment:

• Immunotherapy can be effective in treating cancers that do not respond to other treatments (surgery, chemotherapy, etc). For example, some cancers (like skin cancer) don’t respond well to radiation or chemotherapy but show good response with immunotherapy agents.
• In cases where a cancer is not responding to other treatment methods, the introduction of immunotherapy can help the main treatment method work better.
• As immunotherapy targets the immune system and not the cancer cells, fewer side effects are produced.
• Cancers treated successfully with immunotherapy are much less likely to reoccur. This is so because the body’s immunity adapts and learns to tackle similar cancers later in the future.

The two most common side effects of cancer immunotherapy are:

• Skin reactions:
  • Skin redness
  • Skin blistering
  • Skin dryness
  • Skin can become more sensitive to sunlight
  • Cracks can appear in the skin at fingertips
  • Nail beds can become red, warm, swollen and tender
• Flu-like symptoms: These are common side effects of non-specific immunotherapy and oncolytic virus therapy. The following signs and symptoms can present:
  • Fatigue
  • Fever
  • Chills
  • Weakness
  • Nausea
  • Vomiting
  • Dizziness
  • Body aches
  • High blood pressure or low blood pressure

Other side effects of cancer immunotherapy:

• Muscle aches
• Shortness of breath or trouble breathing
• Swelling of the legs
• Sinus congestion
• Headaches
• Weight gain from retaining fluid
• Diarrhea
• Hormonal imbalances (hypothyroidism can set in due to reduced thyroid hormone production, leading to further weight gain and lethargy)
• Cough

Specific drug-related side effects

• Some common side effects of immune checkpoint inhibitors are:
  • Diarrhea
  • Pneumonitis (inflammation of the lungs)
  • Rashes and itchiness
  • Problems with some hormone levels
  • Kidney infections
• Some common side effects of cancer immunotherapy with monoclonal antibodies are:
  • Allergic reactions, such as hives or itching
  • Flu-like symptoms, like chills, fatigue, fever and muscle aches and pains
  • Nausea
  • Vomiting
  • Diarrhea
  • Skin rashes
  • Low blood pressure
• Some common side effects with adoptive T-cell transfer therapy: Cytokine release syndrome can occur with CAR T-cell transfer therapy; its signs and symptoms may include:
  • Fever
  • Nausea
  • Headache
  • Rash
  • Rapid heartbeat
  • Low blood pressure
  • Trouble breathing
• Some common side effects of cancer immunotherapy immunomodulators: 
  • Drowsiness
  • Fatigue
  • Constipation
  • Low blood cell counts
  • Neuropathy (nerve damage producing pain and loss of sensation in affected area)
• Some possible side effects of cancer treatment vaccines:
  • Flu like symptoms: fever, chills, weakness, dizziness, nausea, vomiting, muscle or joint pain, fatigue, headache, trouble breathing, low or high blood pressure
  • Allergic reactions
  • Stroke is a possible complication with Sipuleucel, a new cancer treatment vaccine designed for use in prostate cancer.
• Some possible side effects with talimogene or V-TEC, the first oncolytic virus therapy approved for melanoma (skin cancer) treatment, are:
  • Tumour lysis syndrome: As the cancer cells die and the tumour mass breaks apart, the components disseminate in the blood. This causes an electrolyte imbalance and can lead to organ damage, especially of the kidneys, heart and liver.
  • Herpes virus infection, which can lead to pain, burning or tingling in a blister around the mouth, genitals, fingers or ears, eye pain, sensitivity, discharge from the eyes, blurry vision, weakness in the arms and legs, extreme fatigue, drowsiness and mental confusion.