The Immune System Strikes Back
How a Lifesaving Treatment can Cause Devastating Side Effects
Author: Katherine Hill
Editors: Sienna Schaeffer, Katie Kelly, Madeline Nicol
Several months ago, a young woman entered the University of Toledo Medical Center ER with blurry vision, fatigue, nausea, and vomiting (1). Two weeks earlier, she had completed a course of an exciting new immunotherapy drug called Nivolumab in an attempt to beat back metastatic melanoma that had continued to spread despite several rounds of chemotherapy.
Now, doctors scrambled to determine what was causing her symptoms. A glucose test revealed that she was suffering from diabetic ketoacidosis; a potentially fatal syndrome that is often the first sign of diabetes (2). At the age of 28, with no personal or family history of diabetes or other autoimmune diseases*, the woman had suddenly developed type 1 diabetes.
New immunotherapy drugs like Nivolumab (trade name Opdivo) and Ipilimumab (trade name Yervoy) represent the cutting edge of cancer treatment. News reports have trumpeted the drugs as a “cancer revolution” in which tumors “melt away” (3). In many ways, the excitement is warranted. One study of patients with advanced melanoma, which generally has a grim prognosis, found that tumors shrank or disappeared completely in 61% of patients who were treated with a combination of Nivolumab and Iplimumab (4).
Despite promising results, immunotherapy has a dark side that is often overlooked. Although the immune system is a potent force for defending the body from invaders, it can be deadly if it turns on the body that it is designed to protect (8). The same study that found dramatic results for Nivolumab and Ipilimumab also found that the combination caused side effects in 54% of patients (4). Many of the side effects reported, such as rashes or diarrhea, are relatively mild for an anti-cancer drug (5). Others, including the sudden onset of diabetes, have been severe or even bizarre (5).
Many of these stranger side effects are a direct result of how immunotherapy fights cancer. Immunotherapy works by encouraging the body’s own immune system to wage war on cancer cells. Unfortunately, when the immune system becomes overactivated, it can begin attacking the very cells that it is supposed to protect. The line can be thin between boosting the immune response enough to fight cancer and sending it careening out of control**.
Nivolumab, Ipilimumab, and other similar drugs are checkpoint inhibitors, which means that they affect the way that T-cells react to specific biological signals. T-cells are a part of the immune system that are responsible for recognizing and targeting threats. When the immune system is functioning normally, the “you” cells have stop signals on their surfaces that tell the T-cells, “I am not an invader so leave me alone.” These signals act as a checkpoint that prevent the immune system from going rogue and attacking the person it is supposed to protect. If T-cells malfunction and direct the immune system to target healthy cells, it can lead to an autoimmune disease such as diabetes or multiple sclerosis in which entire organs can be destroyed or rendered non-functional.
While stop signals are indispensable for anyone who prefers to have all of their organs intact, they can cause problems when cancer cells use the same signals to avoid detection. Because cancer cells are the mutated descendants of healthy body cells, many of them still produce the same stop signals that their unmutated ancestors did. The stop signals prevent an immune response and allow cancer cells to proliferate and spread with little interference.
Checkpoint inhibitors block the T-cells’ response to stop signals, allowing them to pass the stop signal checkpoint and go ahead with their attack. With no stop signal, the immune system is free to attack and destroy the cancer cells that had previously been shielded from it, leading to the dramatic remissions that many patients experience (9). Unfortunately, checkpoint inhibitors prevent the immune system from responding to the stop signals not just on cancer cells, but on all cells. Without stop signals, your cells have no way to signal the immune system to stand down if it turns on healthy cells accidentally (1).
In the case of the young woman from the University of Toledo, researchers found that her blood contained T-cells that were mistakenly programmed to target the beta cells of the pancreas, which produce insulin. These T-cells may have appeared before or after the patient began treatment, but once the treatment began, her body had no way to stop the autoimmune response and all of her beta cells were destroyed. With no insulin, her body was unable to metabolize sugars and she developed diabetes (1).
Although the sudden onset of diabetes appears to be a relatively rare side effect, it is a permanent and potentially deadly condition that should not be taken lightly (5). Diabetes is also not the only autoimmune disease that has been reported in patients taking immunotherapy drugs. Depending on which organ that the immune system attacks, a wide variety of conditions can result. When the immune system destroys the skin cells that produce melanin, patients can develop a condition called vitiligo, where large patches of skin lose their pigment (5, 10). Although vitiligo can dramatically affect appearance, it is not dangerous. The same cannot be said for some of the other autoimmune diseases that patients taking checkpoint inhibitors sometimes experience, including hepatitis, nephritis, and hypothyroidism, among others (5).
For the most part, experts seem to agree that, as serious as the side effects can sometimes be, they do not outweigh the potential benefit to patients (4, 5). As one patient told the New York Times, “I can deal with diabetes if I can beat melanoma” (11).
As the use of checkpoint inhibitors becomes more common in cancer treatment centers throughout the United States, it is important that doctors and patients know what side effects immunotherapy can have and how to keep an eye out for them. In many cases, quick recognition and treatment can be the difference between life and death for patients experiencing a dangerous immune response. If doctors buy into the hype of immunotherapy drugs as “miracle cures” with no downsides, they may not monitor patients closely enough to catch the signs of an impending disaster before it is too late.
Fortunately, doctors who to stay vigilant for side effects can catch most autoimmune effects before they become life threatening. Once doctors at the University of Toledo realized that the young woman they were treating had developed diabetes, they were able to treat her with insulin and she left the hospital without suffering any serious long-term harm (1). As immunotherapy becomes more common, it is the responsibility of the medical establishment to ensure that the stories of other patients who experience serious side effects have similar happy endings.
*Autoimmune diseases occur when the immune system attacks a part of the body by mistake. Type 1 diabetes is a type of autoimmune disease where the immune system attacks the insulin-producing cells of the pancreas, leaving the person unable to metabolize sugars.
**The danger of crossing this line was starkly illustrated during a 2006 Phase 1 Trial for one of the first ever immunotherapy drugs. It was the first time that the drug, TGN1412, was tested in humans. All six of the participants who were injected with the drug had to be rushed to the Intensive Care Unit after experiencing a severe immune response that led to multiple organ failure (6, 7). Although all six participants did survive their harrowing experience, the trial remains one of the most infamous research scandals in recent history (6).
References
1. Hao, J. B. et al. Development of Type 1 Diabetes after Cancer Immunotherapy. AACE Journal Preprint, (2016).
2. Mayo Clinic Staff. Diabetic ketoacidosis. Mayo Clinic (2016). Available at: http://www.mayoclinic.org/diseases-conditions/diabetic-ketoacidosis/basics/definition/con-20026470. (Accessed: 24th December 2016)
3. Herper, M. Immune System Drugs Melt Tumors In New Study, Leading A Cancer Revolution. Forbes Available at: http://www.forbes.com/sites/matthewherper/2015/04/20/immune-system-drugs-melt-tumors-leading-a-cancer-revolution/. (Accessed: 27th December 2016)
4. Postow, M. A. et al. Nivolumab and Ipilimumab versus Ipilimumab in Untreated Melanoma. New England Journal of Medicine 372, 2006–2017 (2015).
5. Hofmann, L. et al. Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy. European Journal of Cancer 60, 190–209 (2016).
6. Wood, A. J. J. & Darbyshire, J. Injury to Research Volunteers — The Clinical-Research Nightmare. New England Journal of Medicine 354, 1869–1871 (2006).
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8. Mayo Clinic Staff. Multiple Sclerosis. Mayo Clinic Available at: http://www.mayoclinic.org/diseases-conditions/multiple-sclerosis/home/ovc-20131882. (Accessed: 28th December 2016)
9. Disis, M. L. Mechanism of Action of Immunotherapy. Seminars in Oncology 41, S3–S13 (2014).
10. Mayo Clinic Staff. Vitiligo. Mayo Clinic Available at: http://www.mayoclinic.org/diseases-conditions/vitiligo/basics/definition/con-20032007. (Accessed: 29th December 2016)
11. Richtel, M. Immune System, Unleashed by Cancer Therapies, Can Attack Organs. The New York Times (2016).
