By releasing the brakes that cancer cells impose on the immune system, researchers are now developing a new generation of powerful treatments against malignant diseases
In June 2004, I was asked to check on a 22-year-old woman who had just graduated from college and was engaged. In the months before graduating, Shirley (pseudonym) suffered from a bothersome cough. Finally, a computed tomography (CT) scan showed multiple nodules in and around her lungs. A biopsy revealed that it was melanoma metastases that had spread from a skin cancer that Shirley didn't even know existed. She immediately began chemotherapy treatments and hastily changed the wedding date.
Unfortunately, two rounds of chemotherapy and radiation to her brain within two years of the discovery slowed, but did not stop, the spread of the cancer. Shirley's options were running out. I told her about a new study in which they were testing an innovative drug aimed at stimulating the immune system against cancer.
Although it was a randomized trial, which meant that only a few of the participants would receive the new drug, then called MDX-010, Shirley agreed to participate. After four treatments, a new series of CT scans showed that the melanoma had disappeared without a trace. To this day, Shirley is in complete remission of the disease. She has two healthy, beautiful children and, as she puts it, "got her life back."
For me, a cancer expert and researcher, Shirley's transformation gave validity to many years of hopes that scientists would indeed succeed in developing powerful drugs for cancer, by activating the body's immune system against the malignant disease. The level of optimism of the medical community increased in 2013 when we learned about similar successes of this treatment and similar treatments in patients with leukemia, kidney cancer and lung cancer in advanced stages. Although immunotherapy, by no means, is not a panacea for all diseases, the progress achieved recently allows us to treat advanced stages of cancer in a much better way than was possible in the last decades.
layers of protection
The feeling that the immune system can take over cancer is not new. Attempts to harness the body's defense systems against malignant diseases began more than 100 years ago when William Cooley, a surgeon at the New York Cancer Hospital (now the Memorial Sloan Kettering Center), tried to use for this purpose bacteria that had been killed by heating. After noticing that some of the patients tended to live longer if they contracted an infection after the cancer surgery, Cooley hypothesized that the body's internal defense systems, activated by the infection, also attacked the tumor.
Over the past decades, scientists have learned a lot about the cells that make up this defense system, and the chemical mediators and molecular switches that carefully regulate it. During this time, they learned how the immune system moves quickly to locate potentially dangerous pathogens, such as bacteria or viruses. The researchers also learned about the many important control systems that limit the immune system so that it does not get out of control and destroy too much healthy tissue during the attack. As a result, they gained detailed insights into how the immune system responds to cancer and is activated by it.
The first layer of defense against pathogens is a general response against bacteria and viruses mediated by white blood cells called neutrophils and monocytes. These cells belong to the innate immune system, and their job is to identify certain aspects of the molecular anatomy common to all bacteria or viruses, such as parts of their outer shell, or features in their DNA or RNA structure that differ from those of more developed organisms. Although these white blood cells do not focus on a pathogen or a specific protein, they nevertheless manage to destroy many microbiological invaders, and subsequently produce molecular segments, called antigens, that other players of the immune system recognize as a foreign substance.
Cells responsible for the second layer of defense, known as the acquired immune system, use these antigens as a starting point for a much more accurate response. This response, if successful, creates a living memory of the invading pathogens so that they can be identified more easily in the future. At the base of the acquired reaction are two types of cells: T cells and B cells.
There are different types of T cells, but they are all descendants of progenitor cells that originate in the thymus gland, a small organ located just above the heart, in the center of the chest. B cells are produced in the bone marrow and are responsible for creating antibodies. The antibodies and certain molecules on the T cells target appropriate antigens, thereby enabling the immune system to target the bacteria or infected cells that display these antigens on their surface and destroy them.
When the immune system is functioning optimally, the innate branch and the acquired branch work together to identify dangerous invaders and get rid of them. In addition, a subset of T-cells retain a long-term molecular memory of the original threat so that if it recurs in the future it can be neutralized more quickly.
It is understood that a cancerous tumor is not a bacterial infection. Cancer is formed when the body's own cells undergo certain genetic and other changes. Despite this, the immune system is supposed to recognize cancer cells because they present on their surface fragments of abnormal molecules, foreign to T cells and B cells. For various reasons, the immune system often fails in its war on cancer. Efforts over the years to try to boost the immune response have produced mixed results. However, recent studies take a different approach and lead to more consistent successes. It turns out that sometimes the cancerous tumor takes advantage of the normal off switches of the immune system, weakening its response to the malignant cells. The new approaches try to remove these restraints.
checks and balances
The experimental drug that saved Shirley's life belongs to this new approach. It arose from research on a protein known as CTLA-4, which is found in many types of T cells, but only comes into action after certain T cells recognize their target and receive a "green light" from other molecules. When clearance is activated, CTLA-4 and several other proteins act as a series of brakes or checkpoints that prevent the immune system from becoming too destructive.
The need for these control points becomes clear when they are missing. Mice genetically engineered to lack the CTLA-4 protein die at three to four weeks of age. When there is no one to restrain the immune system, activated T cells penetrate all the normal organs of the body and completely destroy them. The finding, published in 1995, showed that a persistent deficiency in this single molecule can cause a fatal autoimmune reaction.
That same year, James Ellison, then working at the University of California, Berkeley, hypothesized that if the molecular inhibitor CTLA-4 could be temporarily silenced, the immune system would be able to attack cancer cells more vigorously, and tumors would shrink. Ellison and his colleagues decided to test the hypothesis in mice by introducing a synthetic antibody that impairs the activity of CTLA-4.
Indeed, blocking the activity of CTLA-4 caused the regression of several tumors implanted in laboratory mice, including colon cancer and sarcoma. In other experiments, melanoma tumors shrank significantly when mice were treated with an antibody that blocks CTLA-4 and an experimental vaccine made from melanoma cells modified to trigger a targeted immune system attack on the tumor.
The next step was to try this approach, known as immune checkpoint blockade, in humans. Ellison turned to the biotechnology company Medarex, which developed a human version of the antibody that blocks CTLA-4 (the antibody was first called MDX-010 and now ipilimumab), and began clinical trials in patients who suffered from extremely advanced cancer that did not respond to other treatments. Medrex was eventually bought by Bristol-Myers Squibb (BMS), which continued to develop the drug and received approval to market it in 2011.
Already in the first experiment as well as in the subsequent experiments, there was a very noticeable regression of the tumors in some of the patients. But before that happened, the initial tests that tried to assess whether the treatment was successful produced strange results. The researchers soon realized that when it comes to immunotherapy, the usual ways to test the success of treatment can be confusing.
Success rates
Oncologists can often tell fairly quickly how a patient is responding to standard cancer treatments. We use a variety of imaging methods, computed tomography (CT), positron emission tomography (PET) or magnetic resonance imaging (MRI), to measure the size of the tumor before treatment and after about six weeks. If the tumor is considerably smaller, we can decide to continue the treatment, because we know it has an effect, or consider another approach, or even stop the treatment altogether.
Such decisions during immunotherapy are not made so directly. First, we need to allow a longer time to allow the immune system to wake up, so we usually don't measure tumor size until 12 weeks after starting treatment. But even when we factored in the extra six weeks of observations and treatment, the results of the CTLA-4 blocking trials were confusing. In some patients the scans showed a clear improvement, while in others the tumors grew and new tumors even appeared. But surprisingly, even patients whose tumors had spread felt better.
Today we can come up with two possible explanations for the spread of tumors after immunotherapy: the treatment does not work, or a large number of T cells and other cells of the immune system began to flood the tumor. In other words, a larger tumor may, paradoxically, be evidence that the treatment is working. We just have to wait a little longer to see the tumors shrink. Given the difficulty of measuring progress during immunotherapy, researchers testing ipilimumab now use the simple but important measure of overall survival (how long patients live) as the most appropriate metric for analysis
The results of the studies
The results of the most recent clinical trials show that slightly more than 20% of patients with metastatic melanoma treated with ipilimumab show long-term control of their disease and live at least three years from the start of treatment. This is an important statistic because before the development of modern drugs like ipilimumab, the median life expectancy in metastatic melanoma was seven to eight months. Indeed, some of the first patients, like Shirley, are still alive more than five years after treatment.
Meanwhile, progress has been made in researching another molecule that inhibits the immune system and is found on the surface of many T cells, known as PD-1. When certain other molecules bind to it, PD-1 forces the cells in which it is found to destroy themselves, a natural process that helps, as in the case of CTLA-4, stop the immune response to prevent damage. However, some cancer cells protect themselves by covering their surface with molecules that deceive the PD-1 proteins on T cells and cause the cells to destroy themselves too early. As a result, any T cell that attacks the cancer cell receives a signal to destroy itself. This amazing example is one of the many ways in which cancerous tumors suppress the immune system.
Half a dozen companies, BMS, CureTech, EMD Serono, Genentech, Merck and MedImmune, have all developed antibodies that prevent various tumors from activating PD-1-assisted T-cell suicide signaling. In recent trials, these experimental compounds have induced long-term remissions, sometimes of years, in 30% of patients with advanced melanoma. Some of my colleagues at Memorial Sloan Kettering and colleagues at other centers have tried PD-1 blockers in patients with a certain type of lung cancer. More than 20% of the patients experienced a continuous regression of the tumor.
The results of the lung cancer trials, reported in June 2012, were a turning point in the field of immunotherapy. Skeptical doctors can no longer dismiss the approach as suitable only for a limited number of tumor types, such as melanoma and kidney cancer, which are particularly sensitive to therapies involving the immune system. Immunotherapy also appears to work in a greater variety of cancers. Most likely, this approach will soon join chemotherapy and radiation as a standard treatment for many types of cancer.
As with all cancer treatments, immunotherapy has some side effects. Patients treated with CTLA-4 antibodies, for example, may suffer from an inflammatory reaction in the skin and colon, caused when immune system cells release excess chemicals that trigger an immune response. The rash and painful bouts of colic and diarrhea can be controlled with steroids that suppress the immune response, such as prednisone. Patients treated with PD-1 blockade may also experience an outbreak of the immune system, mainly in the kidneys, lungs and liver, but these are usually less frequent and less severe compared to the CTLA-4 treatments. Fortunately, the use of anti-inflammatory drugs does not apparently impair the healing effectiveness of both drugs.
Inflammation can lead to bigger problems. For a long time, the researchers worried that the triggering chain of events would lead to an acute autoimmune reaction in which it would be impossible to stop the immune system from attacking and destroying increasing amounts of healthy tissue. However, unlike a true autoimmune disease, these inflammatory side effects pass, and do not return after treatment.
Since antibodies against PD-1 and CTLA-4 seem to increase the immune system's response to cancer in different ways, it makes sense to test whether simultaneous treatment with both drugs would be safe and effective. Experiments conducted in 2007, in laboratory animals with colon cancer or with melanoma showed that a combination of CTLA-4 and PD-1 blockers is more effective than the use of each drug separately. For this reason, in 2010, my research group, in collaboration with Mario Schnoll from Yale University, decided to conduct a small-scale study that would examine the safety of treatment with ipilimumab and a drug that blocks PD-1 known as nivolumab, in 53 patients with metastatic melanoma.
The results we reported at a medical conference last year were impressive. In more than 50% of the patients treated with what we believed to be the optimal dose of the antibodies, the tumors shrank to more than half their original size. These reactions differ considerably from the reactions observed after treatment with each individual drug. The side effects were more frequent than after treatment with each drug separately, but it was possible to control them, as before, with the help of corticosteroids. It is important to note that these are preliminary results of a fairly limited experiment, and they may change in a larger or longer experiment. We are currently conducting a comprehensive trial examining a combination of ipilimumab and nivolumab in more than 900 melanoma patients.
Other researchers are testing this combination of drugs to treat lung, kidney, stomach, breast, head and neck, and pancreatic cancer. It is also possible that the addition of a direct attack on the tumor, with the help of chemotherapy or radiation, will make the immunotherapy even more effective, if the cancer cells die in a way that stimulates the innate branch of the immune system. The result may be the perfect medical "storm" that will kill cancer cells and allow the immune system to recognize the cell debris more effectively. Such a combination should also enable the creation of memory cells that will maintain the improved tracking ability against cancer cells long after the treatment has stopped. It has not yet been tested whether it is worthwhile and possible to combine this type of immunotherapy with other types of immunotherapy that are currently being developed, such as vaccines against cancer, to further increase the success of the treatment.
Ultimately, I believe that long-term remissions or even cures of cancer can already be seen as a realistic goal, because we can now combine standard drugs that target the tumor with immunotherapy that stimulates the patients' own defense system.
About the author
Jed D. Wolchok is the Director of the Melanoma and Immunotherapy Service at Memorial Sloan Kettering Medical Center in New York. He advises the pharmaceutical companies Bristol-Myers Squibb, Merck, MedImmune and EMD Serono, but has no financial interest in the success of the drugs mentioned in this article.
More on the subject
Cancer Immunoediting: Integrating Immunity's Roles in Cancer Suppression and Promotion. Robert D. Schreiber et al. in Science, Vol. 331, pages 1565-1570; March 25, 2011.
Nivolumab plus Ipilimumab in Advanced Melanoma. Jedd D. Wolchok et al. in New England Journal of Medicine, Vol. 369, no. 2, pages 122-133; July 11, 2013.
The article was published with the permission of Scientific American Israel
