Over the past few decades, cancer therapy has advanced in leaps and bounds. Despite this improvement (and also spurred on by it), scientists and researchers are constantly looking for newer and better ways to treat cancer patients. Traditionally, cancer patients are treated with chemotherapy, radiation therapy or surgery. Chemotherapy is a treatment that uses drugs and radiation therapy uses high energy waves to kill cancer cells. However, both treatments don’t only affect cancer cells. They can be extremely toxic and have many severe side effects, as they are systemic treatments, meaning that they can affect cells all over the body, including healthy cells. Surgery has limited usefulness, as cancer can spread all around the body to places that are difficult to operate on, or it can spread so much that surgery would be impractical. Because of these reasons, researchers are looking for more effective treatments with fewer side effects, in the hopes of extending the life of patients and allowing them to enjoy life. One of the up-and-coming treatments in the cancer field is called cancer immunotherapy. It is a line of treatment that takes advantage of the immune system and causes immune cells to shrink tumours. This type of treatment has become possible because of the progress that has been made in understanding the human body and its immune system, as well as in-depth research into the ways cancers develop, grow, and evolve.

The immune system is the human body’s defense mechanism against foreign substances or things that may cause disease. These things can be organisms/life forms so small that they are only visible under a microscope. The immune system is mostly made up of the skin, the lining of the gut and lungs, the lymph nodes, and white blood cells, as well as other parts of the body. It recognizes bacteria, viruses, parasites and other infectious agents inside of the body and uses what are called T cells to kill or get rid of the foreign substances. T cells are one of the types of white blood cells that float around the body in the blood. They destroy any of the foreign things that are found in the body. Another type of white blood cell is called B cells. B cells are like security cameras; they recognize pathogens, or foreign substances, through proteins that are found on their cell surface. Once B cells have found a pathogen, they interact with T cells to “inform” them of the invader. The T cells, which are like body guards/security officers, can then find the pathogen and get rid of it. The immune system has evolved in humans to be a highly effective protection and security system against tiny foreign invaders and disease.

Cancer cells develop from normal cells and become mutated so that they can continue to grow without stopping. These mutated cells should be recognized and killed by the immune system but they are often mutated in such a way that they can avoid being destroyed by the immune system. Ideally, the immune system prevents development of cancer by targeting and destroying mutated cells that could cause cancer. Realistically though, cancer cells evolve to avoid detection by the immune system. This can happen in a few ways, including 1) reducing the amount of certain proteins found on the cell surface to prevent detection by the immune system (the B cells), 2) increasing the amount of some cell surface proteins to block the immune system response (the T cells), or 3) causing surrounding cells to release substances that block the immune system and promote tumour growth. Having figured out the ways that cancer cells use to avoid being destroyed by immune cells, researchers can now manipulate cells in the immune system and use them to kill cancer cells and prevent tumour growth.

In the immune system, white blood cells have proteins on the surface of the cells that stop immune cells from attacking healthy cells. One of these proteins is called CTLA4 (cytotoxic Tlymphocyte-associated protein 4). This protein interacts with a corresponding protein that is expressed on cancer cells, and causes T cells to stop working. This prevents cancer cells from being destroyed by the T cells. CTLA4 was first discovered in the late 1980’s, and further research into its biological function confirmed that it is an inhibitory molecule of the immune system, i.e. turning on CTLA4 causes the immune system to stop attacking cells. Once its role was identified, CTLA4 became a subject of interest for researchers trying to control immune response in human diseases. Researchers eventually created antibodies against the mouse version of CTLA4. Antibodies are Y-shaped molecules with ends that are like locks, which recognize specific structures, or keys. Antibodies against CTLA4 can be used to prevent CTLA4 from being turned on, allowing the immune cells to do their jobs. Mice with tumours were used to test the idea of using a CTLA4 antibody to treat cancer, and results were promising. When CTLA4 antibodies were used on the mice, many of the tumours shrunk, and some mice were cured of their cancers. Scientists then made human CTLA4 antibodies, resulting in a drug that was tested in clinical trials and approved by the government (FDA) in 2011 for treatment of skin cancer. This CTLA4 antibody is currently being studied in clinical trials for use in other cancers, such as lung cancer, prostate cancer and bladder cancer. There were actually 2 different CTLA4 antibodies developed by different pharmaceutical companies. One drug has seen great success and has become the more “popular” CTLA4 antibody, as it is the first drug that is thought of when CTLA4 treatment is mentioned. The other drug had some issues in one clinical trial, being unable to show any advantages in comparison to normal chemotherapy treatment. However, this second antibody is still being studied in clinical trials and may prove to be useful in treating some cancers. Many scientists believe that development of cancer immunotherapy will contribute greatly to the fight against cancer, and blocking CTLA4 is one of the major therapies that is being studied to prolong life of a cancer patient.

Another one of the more prominent cancer immunotherapies being studied for use in patients is blocking PD1, another protein found on the surface of T cells. It is similar to CTLA4 therapy, as PD-1 is also used by cancer cells to avoid being killed by T cells. PD-1 stands for programmed cell death protein 1. There are 2 proteins expressed by cancer cells that can bind to and activate PD-1, causing the T cells to be inhibited and allowing the cancer cells to survive. Since the CTLA4 antibody worked so well, researchers decided to do the same thing and developed antibodies against PD-1. Two PD-1 antibodies have been very successful and have been FDA approved for various cancers. One of these two antibodies has been approved for use in 4 different cancers, while the other drug is FDA approved for treatment of 2 different cancers. Both are currently being studied as treatments for other types of cancer. There are also at least 3 more PD-1 antibodies in various stages of clinical trials. PD-1 and CTLA4 antibodies are both looking to be very promising treatments for cancer patients, although these aren’t the only cancer immunotherapy therapies being studied.

Another type of cancer immunotherapy being explored is modified T cells. T cells are taken from a patient, then genetically modified to have proteins on their surface that recognize a specific protein found only on cancer cells. This protein-protein interaction is analogous to a lock and key, similar to the concept of an antibody binding to a protein. These modified cells can be grown and multiplied in the laboratory and then put back into the patient. There is little risk of rejection since the cells were originally from the patient. Once in the patient, the modified T cells can multiply, recognize, and kill cancer cells. The problem with this therapy is trying to figure out a specific protein on cancer cells to target, since many of the proteins that are found on cancer cells are also found on healthy cells. The T cells would bind to anything with the specific protein on it, regardless of whether a cell is healthy or diseased, since it is unable to tell the difference between the two. However, if a protein can be found that is only expressed on cancer cells and not normal cells, this therapy can be used. For example, this therapy has been used in advanced cases of blood cancers such as leukemia and lymphoma, and has resulted in the disappearance of some cancers for extended periods of time. This is a very good sign that the treatment is working well, as usually these cases involve patients with late stage disease, meaning that they are close to death, with few treatment options left to try. Any extension of a patient’s life is good, but with late stage disease, the results of modified T cell therapy are quite miraculous. Although cancer immunotherapy is showing many positive results, it is not without its downfalls.

As with many cancer treatments, costs can be quite high, and cancer immunotherapy is no exception. Some cancer immunotherapies can cost as much as $100,000 per year. Cancer immunotherapy also has side effects, but the benefits of the treatment far outweigh the costs. The side effects of immunotherapy are generally milder than those of chemotherapy or radiation therapy, since immunotherapy is more specific and more targeted towards cancer cells than the other therapies. However, as with most cancer treatments, cancer immunotherapy only works for a certain period of time. Eventually the cancer returns and grows again, meaning that immunotherapy is not a miracle cure for cancer. However, it is another weapon in our arsenal against cancer and can extend a patient’s life for a significant amount of time. Looking at research so far, cancer immunotherapy is showing great promise and has already been FDA-approved for various cancers. Immunotherapy for many other cancers is currently being studied, and while there are obstacles to be overcome, cancer immunotherapy looks to be a huge step in the war against cancer. Some say it’s the best thing since sliced bread, and they might be right, or they might be wrong. Only time will tell…

Future Reading

Ivashko, I. N. and J. M. Kolesar (2016). “Pembrolizumab and nivolumab: PD-1 inhibitors for advanced melanoma.” Am J Health Syst Pharm 73(4): 193-201.

Klebanoff, C. A., S. A. Rosenberg, et al. (2016). “Prospects for gene-engineered T cell immunotherapy for solid cancers.” Nat Med 22(1): 26-36.

Mahoney, K. M., P. D. Rennert, et al. (2015). “Combination cancer immunotherapy and new immunomodulatory targets.” Nat Rev Drug Discov 14(8): 561-584.

Mellman, I., G. Coukos, et al. (2011). “Cancer immunotherapy comes of age.” Nature 480(7378): 480-489.

Pardoll, D. M. (2012). “The blockade of immune checkpoints in cancer immunotherapy.” Nat Rev Cancer 12(4): 252-264.

Pico de Coana, Y., A. Choudhury, et al. (2015). “Checkpoint blockade for cancer therapy: revitalizing a suppressed immune system.” Trends Mol Med 21(8): 482-491.

Preusser, M., M. Lim, et al. (2015). “Prospects of immune checkpoint modulators in the treatment of glioblastoma.” Nat Rev Neurol 11(9): 504-514.

Restifo, N. P., M. E. Dudley, et al. (2012). “Adoptive immunotherapy for cancer: harnessing the T cell response.” Nat Rev Immunol 12(4): 269-281.

Sharma, P. and J. P. Allison (2015). “Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential.” Cell 161(2): 205-214.

Spain, L. and J. Larkin (2016). “Combination immune checkpoint blockade with ipilimumab and nivolumab in the management of advanced melanoma.” Expert Opin Biol Ther: 1-8.

Srivastava, S. and S. R. Riddell (2015). “Engineering CAR-T cells: Design concepts.” Trends Immunol 36(8): 494-502.

Topalian, S. L., C. G. Drake, et al. (2015). “Immune checkpoint blockade: a common denominator approach to cancer therapy.” Cancer Cell 27(4): 450-461.

Ulmeanu, R., I. Antohe, et al. (2016). “Nivolumab for advanced non-small cell lung cancer: an evaluation of a phase III study.” Expert Rev Anticancer Ther 16(2): 165-167.

van der Stegen, S. J., M. Hamieh, et al. (2015). “The pharmacology of second-generation chimeric antigen receptors.” Nat Rev Drug Discov 14(7): 499-509.

Weiner, L. M., R. Surana, et al. (2010). “Monoclonal antibodies: versatile platforms for cancer immunotherapy.” Nat Rev Immunol 10(5): 317-327.