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ADVANCEMENT: The Future of Cancer Vaccines
by David Schoenfeld
As early as the late nineteenth century, doctors working with cancer patients formulated the idea that the body's own immune system could be stimulated to kill cancer cells - it was thought that the body in effect could be "vaccinated" against cancer. It is only recently, however, that researchers have begun to devise effective methods to utilize the immune system's destructive capacity as a form of cancer treatment. Cancer vaccines won't supplant more traditional forms of cancer treatment such as chemotherapy over the next decade, but they do have the potential to radically enhance doctors' ability to halt the progression of cancers, drive them into remission, and prevent their recurrence, while simultaneously reducing the toxic side-effects normally associated with cancer therapy.
The concept of cancer vaccines rests upon exploiting differences between normal cells and cancer cells, which are cells that divide uncontrollably. Specifically, research has focused on the differences in the expression of molecules, either proteins or carbohydrates, found on the surfaces of these cells. These molecules act as antigens, a term that describes any type of substance that interacts with cells of the immune system. If the immune system could be stimulated to act against antigens that are either specific to or over-expressed by cancer cells, these cells would be destroyed by the body's own defense mechanisms-- a process that would be both specific to cancer cells and would not require the addition of toxic compounds. This response does not occur naturally because cancer cells derive from normal cells and thus resemble them closely, making it difficult for the immune system to effectively distinguish between the two types of cells and mount an immune response against the aberrant cells. Cancer cells also have developed methods to suppress the immune system and protect themselves from destruction.1
Progress in developing cancer vaccines is only coming to fruition recently due to the previously held belief that not all cancer cells presented cancer-specific antigens, or differed significantly on their cell surface from normal cells. However, it is now known that all cancers are antigenic, which means that they present a defining set of surface molecules (although there is variation among types of cancer).1 Many cancer-specific antigens are already well characterized, and much current research is devoted to identifying additional cancer antigens. This effort includes a search for cancer antigens that are broadly expressed among different types of cancer that could serve as a basis for "universal" cancer vaccines.
Traditional vaccines operate by injecting specific antigen-presenting substances, or a mixture of them, into the body, which elicits an immune response that includes the production of antibodies directed against the antigens, which eventually leads to their destruction. Subsequently, specific cells of the immune system "remember" the antibodies produced and are capable of initiating their production in massive quantities if the same antigens are again presented. This type of vaccination serves as a preventive measure to future infection by viruses, bacteria, or other foreign bodies bearing the antigens. While preventive (prophylactic) vaccines against cancers have already been developed, these vaccines work by conditioning the immune system to elicit a response to infectious agents, primarily viruses that are responsible for inducing cancers, and not against cancer cells themselves. A vaccine against the hepatitis B virus, responsible for forms of liver cancer, has already been approved by the Food and Drug Administration (FDA), and a vaccine against human papilloma virus, responsible for nearly all cases of cervical cancer, is currently undergoing large-scale human testing.
On the other hand, therapeutic cancer vaccines are intended to prevent the further growth of existing cancers, prevent the recurrence of cancers, and destroy cancer cells not affected by other treatments. This type of vaccine works by introducing cancer antigens into the body, with the hope that the resulting activated immune system will destroy not only the added antigen, but also living cancer cells within the body expressing the cancer antigen. The antigens are sometimes derived from cancer cells taken out of the patient's body, but can also be taken from other individuals with similar forms of cancer or manufactured in a laboratory setting. A variety of methods are currently being investigated to introduce these antigens into the body and elicit an immune response. Whole cancer cells can be removed from the patient's body, subjected to radiation or heat that kills the cells but largely maintains their surface composition, and then be injected back into the patient, where they can initiate an immune response directed at living cancer cells. While this method has the advantage of presenting to the immune system the entire repertoire of cancer cell antigens, many of these antigens may undergo significant changes or be lost entirely during the process of killing the cells, and it is uncertain whether this method sufficiently stimulates the immune system and directs it against live cancer cells. The amount of cancer cells available for removal may also place limitations on this type of cancer vaccination.1
An alternative method involves the use of a special type of white blood cell called dendritic cells (DCs). DCs are responsible for incorporating antigens, and then presenting them to and activating T-cells, the cells which would actively fight cancer cells. Therefore, successful antigen uptake and presentation by DCs is essential to any cancer vaccine treatment. In this method, DCs are taken out of a patient's body, the cancer antigen is introduced, cell maturation is promoted, and the DCs are then inserted back into the patient's body. By removing the DCs from the body, and controlling the uptake of antigens and maturation of the cells, researchers hope to produce efficiently a set of well-differentiated DCs that are optimally suited for inducing an immune response. While its efficacy has been demonstrated in mouse models, this method is a very costly and complex process, and it remains to be seen whether its benefits outweighs the costs.1
An additional method of antigen introduction involves combining one or more cancer antigens, either removed from the patient's own cancer cells or produced in the laboratory, with a weakened protein or bacteria that is known to cause the immune system to mount an attack, known as an adjuvant. The intention is that the antigen-adjuvant complex will be attacked by the immune system, and will subsequently cause cancer cells expressing the antigen to be attacked as well.2
The development of cancer vaccines has progressed significantly recently through the increased understanding of the manner in which the immune system operates and the methods employed by cancer cells to suppress its operation. With this knowledge, researchers are now able to counteract the immunosuppressive properties of cancer cells and stimulate the immune system by adding natural and artificial factors to the body. The net result is an increased ability to activate the immune system in response to antigen introduction and to direct the immune response against cancer cells.2
Despite these advances, many questions remain regarding cancer vaccines. Side-effects have generally been minor and correspond to the usual symptoms associated with vaccination, such as flu-like symptoms and skin irritation at the site of injection. However, as in any therapy that involves the manipulation of the immune system, researchers must make sure that cancer vaccines do not ultimately induce autoimmunity against normal cells. Additionally, although the immune system may be activated following treatment with a cancer vaccine, a clinically important outcome requires a strong, specific response that persists. Furthermore, researchers must confront the fact that cancer cells can mutate over time, and that in doing so, they may evade destruction by the immune system.
There are currently several cancer vaccines undergoing large-scale human trials with the FDA. To accurately determine the effectiveness of cancer vaccines, however, lengthy and expensive clinical trials are still required. Ultimately, although much progress has recently been made in the development of cancer vaccines, they represent a breakthrough that still lays off in the horizon but have the potential to revolutionize the way we treat cancer.
Sources:
1. Gilboa, E. "The Promise of Cancer Vaccines." Nature Reviews Cancer 4: 401-411 (2004).
2. http://www.cancer.gov/newscenter/benchmarks-vol3-issue1/page2
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