How Things Work: Immunotherapy

The immune system is an amazing ensemble of organs, cells and substances that work to identify and fight off foreign agents, such as bacteria and viruses. It attempts to keep an individual free from illnesses and infections. But did you know, thanks to recent research in the past few decades, that with the appropriate treatment, the immune system could be instrumental in curing cancer, one of the leading causes of death in America?

Known as immunotherapy, the treatment has joined the ranks of other forms of cancer treatment, including surgery, radiation, chemotherapy, and targeted therapy. Cancer involves the uncontrollable growth of cells, or tumors, in the body, and the aforementioned treatments are designed to kill off the tumors. But what differentiates immunotherapy from other forms of cancer treatment is its efforts to bolster the body’s natural defenses in fighting cancer. A complex disease, cancer thrives when it goes unnoticed by the immune system, as cancer cells can appear very similar to normal cells. In other cases, the immune system may recognize the cancer cells as harmful, but do not provoke a strong enough response to stop the cancer.

To address the issues, scientists developed different kinds of immunotherapies. Cancer vaccines are one such kind. Similar to the way vaccines expose the body to weakened forms of infections in order to strengthen the immune response to the infection, cancer vaccines are designed to enhance immune system attack on cancer. Such a feat is accomplished by exposing the body to harmless or weakened, entireties or pieces of cancer cells. The body may also be exposed to antigens from the cancer through the vaccines. Antigens are proteins that induce the immune response. Despite its evidence of its promise, cancer vaccine have so far shown limited effectiveness in treating cancer.

A more major type of immunotherapy involves the administration of proteins called monoclonal antibodies. When injected into and circulated in the bloodstream, the antibodies recognize and bind to antigens, in a manner reminiscent of fitting a key to its appropriate lock. Hence, antibodies can be designed to bind to the antigens that are found on cancer cells, allowing the cancer to be marked for destruction by the immune system. A monoclonal antibody can work by itself, or it can also be structurally joined with other components, such as a chemotherapy drug, radioactive particle, or another monoclonal antibody.

Another type of immunotherapy, and the most widely used, uses immune checkpoint inhibitors, which also employ the use of monoclonal antibodies. According to the American Cancer Society, checkpoint inhibitors can be thought of as drug that “take the "brakes’ off" of the immune system.

The purpose of checkpoints is to ensure that normal cells do not get attacked as immune cells attack potentially harmful agents in the body. However, with the help of the checkpoints, cancer cells can find ways to evade the detection of the immune system. Inhibitors of the checkpoints would help to prevent that evasion.

In the 1980s, the checkpoint, CTLA-4, was discovered by French scientists. CTLA-4 is a protein that can be found on T-cells, which serve as a form of offense for the immune system. In a 1996 paper from the journal Nature, James P. Allison, a scientist at the University of California, Berkeley, stated that antibodies could target and bind to CTLA-4. Thereby, the antibodies could suppress activity of CTLA-4, and in turn, help to boost the activity of T-cells, which would ultimately enhance the immune system’s ability to fight cancer cells. Later on, in 1999, scientists at Medarex, a former American biopharmaceutical company, initiated development of the antibodies that were proposed by Allison. Once the antibodies, or checkpoint inhibitors, were developed and tested for appropriate safety and efficacy, the Food and Drug Administration (FDA) approved the drug in 2011. Known as an anti-CTLA-4 therapy, Yervoy is used to treat advanced-stage melanoma, a common type of skin cancer.

Clinical successes seen from anti-CTLA-4 therapy helped to establish the field of immunotherapy. Other checkpoints have also been discovered, concurrently with the development of Yervoy, including proteins called PD-1 and PD-L1. Therapies for the checkpoints were also developed in drugs, including Keytruda and Opdivo, which are used to treat certain kinds of cancer. Sometimes, a few different checkpoint inhibitors are applied in combination to increase the efficacy of the immunotherapy in patients. Researchers also hope to use checkpoint inhibitors in combination with cancer vaccines.

Yet, despite the effectiveness of the antibody therapy in some patients, the drugs do not actually work for the majority of patients due to a variety of factors, such as having certain kinds of genes that make the immunotherapy less effective. Immunotherapy treatments can cause severe and fatal side effects through overstimulation of the immune system. Furthermore, immunotherapy drugs are expensive, costing as much as a few hundred thousand dollars a year.

While researchers are have much to do to improve such a form of cancer treatment, immunotherapy brings the hope that a more definitive cure for cancer will be developed in the near future.