Scientists and prostate cancer patients alike cheered when the FDA approved Provenge, the first therapeutic vaccine for prostate cancer, in April 2010. A few months later, a second group of researchers published a clinical study that suggested the potent effects of ipilimumab, an antibody-based drug, in fighting advanced melanoma, a form of skin cancer. Provenge and ipilimumab are just two of several emerging cancer therapies that harness the body’s immune system in the battle against cancer. As we look forward to the discovery of more cancer immune therapies in the future, it is worthwhile to note that scientists have not always appreciated the link between the immune system and cancer cells.
The immune system: guardian against infections
The immune system is an assortment of cells, organs and substances that help protect the body from infections and diseases. Every day, the immune system encounters an overwhelming amount of material, both self and foreign. However, it is able to discriminate between the two such that only harmful foreign invaders like bacteria, viruses and parasites are attacked while “friendly” self tissues are left alone. This is because microbes often contain substances such as proteins and carbohydrates that are absent or markedly different from those found in the body.
Specialized immune cells known as macrophages and dendritic cells are remarkably efficient at sensing these unfamiliar microbial products and quickly react to an offensive bug in a number of ways. For instance, they can engulf the microbe and slowly digest it within themselves. At the same time, they begin to release copious amounts of chemicals that sound the alarm to the rest of the body, causing a variety of other immune cells to swarm towards the site of infection. Amongst these recruited cells are B cells, which produce antibodies, and T cells, which can kill the microbe or infected cell directly or secrete more powerful substances to boost the activity of other immune cells. Collectively, the rapid influx of immune cells and coordinated production of anti-microbial chemicals is called inflammation and helps to keep foreign invaders at bay.
Does the immune system “see” cancer cells?
Unlike microbes, cancer cells present a unique conundrum in that they are derived from the body’s own cells. Cancer cells have been transformed by mutations in their DNA, causing them to grow uncontrollably and form tumors, but otherwise closely resemble healthy cells in the body. As a result, many scientists were skeptical about the capacity of the body’s immune system to discriminate between cancer cells and normal tissues, and thus “see” the cancer.
Research over the years has shown that the immune system is indeed able to distinguish between healthy and cancer cells. The first evidence to support this idea came from human and mouse studies which demonstrated that T cells can respond to cancer cells by directly killing them or producing anti-cancer substances when both cell types are mixed together outside of the body. Researchers subsequently identified specific proteins from a variety of cancer types that can be recognized by T cells.
Support for cancer immunity also arose from clinical observations that the number of T cells present in a tumor is better at predicting disease outcome than conventional methods such as tumor stage and appearance. Moreover, people who have received organ transplants suffer cancers at rates more than seven times higher than those in the general population. Since transplant recipients have to be on long-term medication that suppresses the immune system to prevent graft rejection, scientists surmised that the weakened immune system in these patients is less effective at eradicating any cancer cell that develops.
The mechanisms by which the immune system distinguishes cancer cells from normal cells remained murky until the last decade. Scientists now know that dying cancer cells release special molecules called “danger signals”, which can activate macrophages and dendritic cells as potently as bacteria and viruses. Another kind of immune cell, known as the natural killer cell, can also detect and destroy cells that are “stressed” or abnormal due to infection or cancerous transformations. In addition, many genes that are mutated in cancer cells trigger inflammation in the vicinity of the tumor. Inflammation helps to recruit immune cells to the cancer site and mobilize them against the growing tumor.
Taming cancer cells: cancer dormancy
Sometimes the body’s immune defenses prevent the development of large, life-threatening tumors by maintaining cancer cells in a state of dormancy or “equilibrium.” In this case, the cancer is neither progressing nor regressing. According to a report published last year, T cells are involved in this process, helping to keep melanoma cells in a dormant condition for sustained periods of time in mice.
Understanding that the body’s natural defenses against cancer do not necessarily “cure” the cancer is an extremely important insight. There have been rare organ transplant scenarios in which melanoma was transmitted from a donor to multiple recipients after transplantation. In all cases the donor had a history of melanoma but was free from disease at the time of organ graft. One donor had been clinically cancer-free for 16 years, and another for 32 years. It now seems likely that these donors were not genuinely cancer-free, but rather harbored dormant cancer cells that “awoke” after transplantation and grew aggressively upon transfer into the new, immune-suppressed host. Our growing knowledge of cancer cell dormancy will help doctors prevent this tragic event from occurring as often in the future.
Looking ahead: using the immune system to combat cancer
As scientists learn more about cancer immunity, they become increasingly adept at using the body’s natural immune armament as a tool to battle cancers. For example, T cells that recognize specific cancer proteins are being tested in early clinical trials for the treatment of melanoma, and to date have shown modest success. Provenge, the FDA-sanctioned prostate cancer therapeutic vaccine, consists of dendritic cells which are actually isolated from the patient and “educated” in the lab to detect cancer cells. The educated dendritic cells can then activate other components of the body’s immune system, including T cells.
More recently, scientists found that advanced melanoma patients treated with ipilimumab lived longer than those who did not get the drug. Ipilimumab is an antibody that blocks the activity of a protein that dampens immune responses, thus freeing the immune system to assault the cancer more vigorously.
As with any new experimental treatment, there remain several important caveats to the use of Provenge and ipilimumab. Neither therapy prolongs the median survival rate in treated individuals by longer than 5 months. The personalized nature of Provenge also means that the vaccine comes with a hefty price tag. Nonetheless, as Dr. David Penson, who worked on the original Provenge studies, said: “For someone who’d have 18 more months to live, you get 20 percent more life,” when treated with Provenge.
At the same time, scientists are coming up with newer and more promising immune therapies for cancer. One such drug is Ontak, which was originally used to treat T cell lymphoma and has recently exhibited clinical activity when administered to advanced melanoma patients. Ontak acts similarly to ipilimumab, releasing the brakes on the immune system by depleting a cell type that normally restricts immune responses. Ontak is now going into the final phase of clinical trials. As we await the results from the Ontak study, we can be confident that the next decade will witness the advent of newer, better, and cheaper forms of cancer vaccines and immune therapies.
Tze G. Tan is a graduate student at Harvard Medical School.
For more information:
An overview of the human immune system: http://www.thebody.com/content/art6319.html. For more detail, visit the National Institute of Allergy & Infectious Diseases website on the immune system: http://www.niaid.nih.gov/topics/immunesystem/pages/default.aspx
An informative multimedia website explaining how cancer cells differ from normal cells:
An overview of cancer immunology and immune therapies: Oliver J. Finn. 2008. N Engl J Med 358:2704-2715.
Immunosurveillance of melanoma cells in mice: Eyles J et al. 2010. J Clin. Invest. 120(6):2030-9.
Transmission of donor melanoma by organ transplantation. 2010. Lancet Oncol. 11(8): 790-796.
A review of cancer immune therapy by the American Cancer Society: http://www.cancer.org/Treatment/TreatmentsandSideEffects/TreatmentTypes/Immunotherapy/index
Coverage of ipilimumab in the news: http://www.nytimes.com/2010/06/06/health/research/06cancer.html?_r=1&scp=1&sq=cancer%20immunology&st=cse
FDA approval of Provenge in 2010: http://abcnews.go.com/Health/MensHealth/life-extending-prostate-drug-provenge-garners-fda-approval/story?id=10511290