Immunotherapy is a type of treatment that stimulates or restores the body’s own immune system to fight infection and disease. There are various types of immunotherapies used to treat cancer today, and still more being developed and used in clinical trials.
Natural antibodies are produced by B cells to target and bind to specific cell-surface antigens. The antibodies then direct other immune cells to attack cells containing the antigen.
Antibodies can also be designed and produced in a lab, and many millions of copies made. These are called monoclonal antibodies due to their identical structure. Most are referred to as passive immunotherapies because they directly bind to cancer cells. Others act as active immunotherapies because they target immune cells as well, and help them find cancer cells.
Naked monoclonal antibodies have no drug or radioactive material attached to them, and are the most common. Some attach to cancer cells and attract immune cells to destroy them. Some act as checkpoint inhibitors, and others block antigens that help cancer cells grow.
Antibody-drug conjugates are antibodies that carry a chemotherapy drug or radioactive particle, and deliver these toxic substances directly to the cancer cells. This can potentially reduce side effects experienced with traditional chemo- and radiotherapies, which circulate indiscriminately throughout the body.
Bispecific antibodies are a combination of two different monoclonal antibodies that can bind to two different targets. Some are called bispecific T cell engagers (BiTEs), which bind to both an antigen on cancer cells and a protein on T cells, thus bringing cancer and immune cells together.
Adoptive cell therapy
Also known as cellular immunotherapy, adoptive cell therapy uses T cells to fight cancer.
As discussed earlier, the immune response may be too weak for an effective anti-tumor response. This could be due to the fact that T cells must be activated before attacking cancer cells, and must maintain this activation for a long time in order to be effective. Moreover, T cells may not be found in sufficient numbers in the body.
Tumor-Infiltrating Lymphocyte (TIL) therapy harvests T cells found in or near the patient’s tumor. These cells are tested in a lab to determine which ones best recognize the tumor, and those selected are then grown in large numbers and activated. The idea is that once reintroduced into the patient, the sheer number of T cells will be able to overcome any signals the tumor is releasing to suppress the immune response.
Not every cancer patient has T cells that recognize their tumors or are able to be expanded to sufficient numbers in a lab. Engineered T Cell Receptor (TCR) therapy may be a good option for these patients. In this approach, the patient’s T cells are equipped with a man-made T cell receptor that targets a specific antigen found on the patient’s tumor cells. These highly-personalized T cells are then re-infused back into the patient in large numbers, providing a greater chance of eliminating the cancer.
It’s important to note that TIL and TCR therapies can only target cancer cells whose antigens have been broken down into short fragments by specialized immune cells. Chimeric Antigen Receptor (CAR) T cell therapy, however, allows T cells to bind to cancer cells with naturally-occurring cell-surface antigens. The range of potential antigen targets is smaller than with TIL or TCR therapies.
CAR T cell therapy involves genetically altering the patient’s T cells in a lab by adding a synthetic receptor, called a chimeric antigen receptor (CAR), specific to the patient’s cancer. A large number of CAR T cells are made before reintroducing them into the patient to drive a targeted immune response.
Regardless of whether a cancer vaccine is preventative or therapeutic, the hope is that the vaccine will continue to work long after it’s given. This is because the immune system has specialized memory T cells that remain after infection and provide a rapid response upon re-exposure to a repeat antigen.
Preventative cancer vaccines reduce the risk of certain cancers that are caused by viral infections. For example, human papilloma virus (HPV) has been linked to cervical and throat cancer, while hepatitis B virus (HBV) increases the risk of developing liver cancer. These vaccines do not target cancer cells, but are traditional vaccines that target viruses.
Therapeutic cancer vaccines teach the immune system what cancer cells “look like”. They help immune cells to recognize antigens found on tumor cells that are absent from, or found in low numbers on, normal cells.
These therapeutic vaccines can be made in three ways:
- Custom-made from the patient’s own tumor cells to illicit an immune response against the patient’s unique cancer.
- Made from tumor-associated antigens found in many people with a certain type of cancer.
- Made from the patient’s own dendritic cells, which are immune cells that stimulate the immune system.
Oncolytic virus therapy
This therapy, which uses viruses to infect and destroy cancer cells, is sometimes referred to as a type of therapeutic cancer vaccine.
This therapy is promising because:
- cancer cells are vulnerable to viral infection.
- these viruses can be engineered to have minimal impact on healthy cells.
- as the virus replicates, it causes cancer cells to burst, releasing new viruses and antigens that stimulate immune cells to seek and destroy remaining tumor cells.
These drugs act on pathways that regulate the immune system, either by pressing the “gas pedal” or putting on the “brakes”.
While it’s important for the immune system to respond to foreign invaders in a powerful way, an over-zealous immune response can damage healthy cells. To prevent this, cells in the body are able to slow the immune system by using receptors on their surface, called “checkpoints,” to bind T cells and inhibit their response. Cancer cells exhibit an abundance of these checkpoints, thereby preventing the destruction of the tumor.
Checkpoint inhibitors are drugs that block these proteins, allowing T cells to recognize and attack cancer cells. These types of drugs, which don’t directly affect the tumor, are the most widely used immunotherapy.
Cytokines are proteins that are important in controlling the growth and activity of immune and blood cells. They coordinate the immune response and send signals that can help abnormal cells die and prolong the life of normal cells. Some cytokines help immune cells to grow and multiply more quickly, while others boost certain cells’ ability to attack cancer cells.
Agonists activate pathways involved in adaptive immune responses, while adjuvants activate those involved in innate immune responses.
NK cell therapy
As part of the innate immune system, NK cells recognize and attack anything that appears to be abnormal, unlike T cells that respond only to a specific antigen on the surface of a foreign cell. This broad action makes NK cells an attractive choice for cellular immunotherapies.
Several clinical trials are underway using NK cells collected from peripheral blood, umbilical cord blood, or generated from stem cells. Some researchers are testing the use of unmodified NK cells, while others are engineering NK cells in various ways.
CARs have been added to NK cells in order to make them more effective at targeting cancer cells while sparing healthy cells. Genes coding for a protein that encourages NK cells to divide faster and live longer have been engineered into the cells. So far, NK cells do not appear to cause any of the significant toxicities associated with CAR T cell therapy, such as graft-versus-host disease.
Personalized neoantigen vaccines
Tumors often over-express normal antigens, but can also express new antigens that arise as a result of mutations. These are called neoantigens and are not found on any of the body’s healthy cells.
Neoantigen vaccines that precisely target a patient’s tumor cells without affecting healthy cells are currently being developed, and their efficacy is being investigated in clinical trials.