By Will Donnellan, M.D.
In 1911, William B. Coley, a bone sarcoma surgeon (i.e. modern day orthopedist) in New York City began to inject bone tumors with bacterial toxins. He affectionately referred to his therapy as “Coley’s toxins”. Amazingly, some of the tumors began to shrink. At the time Dr. Coley did not know the mechanism by which his toxins were working. We now know that the bacterial toxins probably had no direct effect on the tumor. Alternatively, the toxins were attracting immune cells into the tumor. Once within the tumor the immune cells were recognizing the tumor as abnormal and attacking it. Unknowingly, a new form of cancer therapy that would one day be called immunotherapy had been born.
Over the last 100 years, there have been great strides in our understanding of the complicated relationship that exists between the immune system and cancer. In 1967 it was discovered that vaccinating chickens against an alpha-herpes virus prevented the development of a certain type of avian lymphoma. Years later it was proven that some human cancers could be prevented by immunization against viruses such as the human papilloma virus (HPV) and hepatitis B virus (HBV). More recent efforts have focused on stimulating the immune system to fight cancer after it is established in the body.
The immune system is able to recognize cancer cells in several different ways. By one mechanism, tumor cells often display markers on their cell surface that are not displayed on normal cells. These markers are called tumor specific and tumor associated antigens. These antigens mark the tumor cells as diseased or abnormal, so that our immune system is then able to recognize and kill them.
But if the immune system is so easily able to destroy cancer cells then why does cancer ever develop at all? The answer is that over time cancer cells evolve and adapt to evade the immune system. They stop displaying the tumor antigens on their surface and are therefore able to hide from the immune system. Additionally, they begin to wage their own war against our immune system. Using certain cancer cell receptors they engage our immune cells and transmit signals that turn the cells off. When the immune cells are turned off, they become tolerant of the cancer and it is allowed to grow and spread.
Efforts have therefore been made to prevent or reverse the suppressive effect that cancer has on the immune system. The first attempts at activating the immune system against cancer occurred in the field of melanoma. A hormone known as IL-2 was given to patients which stimulated the immune system to wake up and attack the cancer that was trying to suppress it. While this treatment occasionally worked, it was effective in only a small percentage of patients and was very toxic.
Recently, a less toxic and more effective class of medications called the “checkpoint inhibitors” have been developed. These medications work by blocking the signals that cancer cells use to turn off the immune system. The first medication in this class to be approved, ipilimumab or Yervoy, is effective in patients with metastatic melanoma. The second medication to be approved, pembrolizumab or Keytruda, is also effective in metastatic melanoma. Additional checkpoint inhibitors are showing promise in other types of cancer including lung cancer, bladder cancer, and Hodgkin’s Lymphoma.
Unfortunately, checkpoint inhibitors are not universally effective in all types of cancer. Therefore, other forms of immunotherapy have been developed. In acute lymphoblastic leukemia a medication called blinatumumab or Blincyto was recently approved for patients who have relapsed following chemotherapy or a stem cell transplant. This medication is composed of a protein with two ends that have been fused together. One end binds to the leukemia cell and the other end binds to an immune cell. When the medication is bound to both cells simultaneously it pulls them into close physical proximity so that the immune cell can kill the leukemia cell. The immune cell doesn’t even have to recognize that the leukemia cell is a cancer cell. The medication is doing this job for it. This treatment is able to achieve remissions in a large percentage of patients who otherwise would not have many other treatment options.
Maybe even more exciting, there are efforts underway to genetically engineer immune cells (specifically T-cells) to recognize and kill tumor cells. Most of the work to date has been done in patients with acute lymphoblastic leukemia and certain types of B-cell Non-Hodgkin’s Lymphoma. This therapy is known as chimeric antigen receptor (CAR) modified T-cells. The CAR modified T-cells are manufactured by removing T-cells from the body and transporting them to a lab. Once in the lab they are infected with a genetically modified virus. By very complex mechanisms the virus causes the T-cell to start making a leukemia-recognition receptor on its cell surface. The T-cells are then stimulated to multiply and when they accumulate in sufficient numbers they are re-infused back into the patient. The T-cells then circulate through the body and when they come in contact with a tumor cell they are able to use the leukemia-recognition receptor to bind the tumor cell and kill it. While not yet FDA approved, this therapy has been successful in many patients whose cancer has become unresponsive to standard treatments and it remains under clinical development.
The field of cancer immunotherapy is exciting and is rapidly evolving. All immunotherapies that are currently FDA approved are available through Tennessee Oncology. Additionally, by way of the partnership between Tennessee Oncology and Sarah Cannon Research Institute many of the immunotherapies under development are available through clinical trials.
Over 100 years ago William Coley had the idea of injecting bacterial toxins directly into tumors to shrink them. If Dr. Coley were around today it would be to his chagrin that it was not his eponymous toxins that were shrinking the tumors, but rather the response of the immune system to the toxins. A century of cancer research has refined his rudimentary techniques into sophisticated immunotherapies that are helping patients on a daily basis. As these therapies continue to develop there is reason to believe that many patients will benefit or even be cured by efforts that started with a NYC bone surgeon who in 1911 began injecting his “Coley’s toxins” into tumors.
