Cancer Vaccines

A friend of mine recently asked me whether or not I believe excessive cell phone use can cause cancer. Like your favorite radio station, cell phones use wavelengths longer than those of visible light. So I told her that unless someone can come up with a good reason why light bulbs cause cancer, I think there is no reason to be afraid. But my friend’s question did remind me of the constant possibility of developing cancer that threatens young, old, and even the most health-conscious among us. While browsing journal articles related to cancer treatment and prevention, I found some potentially very good news in a review article by C. Palena and J. Schlom.¹ In recent years, biologists have made discoveries concerning our immune response to cancer that may dramatically increase the efficacy of future cancer vaccines. I thought I’d explain some of the developing technology in this blog:

The major histocompatibility (MHC) genes are contained within the nucleus (the part of the cell that stores DNA) of each cell in our body. These genes provide the necessary information for cells to synthesize very specific proteins which display other proteins called antigens to the immune system. When a cell is uninfected and healthy, it only displays “self antigens.” However, when a cell is infected, it displays proteins belonging to the infectious agent, “non-self antigens.” The immune system recognizes self antigens but will attack and kill cells displaying non-self antigens. T-cells, a kind of white blood cell, are the specific cells of the immune system that identify antigens as either self or non-self.

Unfortunately, some cancer cells have the ability to suppress the MHC genes. Without the information provided by these genes, cells cannot make the necessary proteins to display antigens. Thus, T-cells cannot identify and kill diseased cells. However, there are other cells of the immune system called natural killer (NK) cells which can sometimes recognize and kill cells which have had their MHC genes suppressed. While this is not a perfect system, it does make it more difficult for cancer to escape detection by the immune system. In studies examining mice and humans, high numbers of NK and T-cells have been shown to significantly slow or even stop the growth and spread of cancer.

One way to bolster the immune system is to add substances known as adjuvants to the cancer vaccine. Cytokines, small regulatory proteins secreted naturally as signaling molecules by cells of the immune system, make excellent adjuvants for cancer vaccines for two reasons. First, some cytokines directly increase the number and effectiveness of NK and T-cells. Second, some cytokines can act on antigen presenting cells to increase antigen presentation and enhance T-cell activity. Researchers have waged successful battles against cancer in pre-clinical trials by genetically engineering tumors to produce one such cytokine called GM-CSF. A drawback to using cytokines, however, is that they have some potential toxicity associated with their use. Research focused on limiting toxic effects is ongoing, and current goals include determining the best cytokine delivery mechanisms and optimally pairing specific cytokines with specific vaccines.

Cancer biologists are also making progress dealing with another of cancer’s many threatening properties. Cancer cells emerge from normal body cells that have acquired mutations in their DNA. Despite these mutations, cancer cells can still have a lot in common with normal cells, including the specific proteins they make. This means that T-cells often recognize the antigens presented by cancer cells as self-antigens because they are the same as the antigens presented by normal cells. A vaccine targeted against self-antigens would be very harmful, or even deadly, because it would combat all cells, including healthy ones. To solve this problem, cancer biologists are working on ways to target tumor-specific antigens. Such antigens are produced as a result of changes in the cancer cell DNA that lead to the synthesis of proteins not present in normal body cells. A vaccine targeted against these antigens would not negatively affect healthy cells because they do not synthesize these proteins. However, in some cases cancer cells can reduce or completely stop producing certain antigens, a technique which helps them avoid detection and destruction by the immune system. Cancer biologists are addressing this problem by targeting proteins that are functionally relevant. In other words, they are developing vaccines that capitalize on proteins that are absolutely required for the cancer cell to survive, grow, or spread to other parts of the body. Thus, if the cancer cell is viable, it will be killed by the vaccine-aided immune system.

An example of a tumor-specific and functionally relevant antigen is the protein Brachyury. Although it is not normally found in adult human tissues, Brachyury is highly expressed by many tumors in epithelial tissue, which forms body surfaces and cavities and is the most likely of all tissues to become cancerous. Additionally, Brachyury allows cancer to spread by helping cancer cells convert to mesenchymal cells, stem cells that can move around and infect other tissues of the body. Studies that have inhibited Brachyury production in Brachyury-positive cancer cells have successfully reduced the cancer’s invasion to healthy tissue. Also, Brachyury can be specifically targeted by vaccines without harming healthy tissue. The proteins Twist, Snail, and Slug, which are also involved in cancer proliferation, will likely be antigens of interest in future research.

Finally, innovative genetic and molecular techniques have made it possible to identify key steps in the onset and spread of cancer. Scientists have been using this newly available information to develop therapeutic drugs that stop certain chain reactions that help cancer advance. They are also investigating the effects of these drugs on the immune system in the hopes that the drugs can soon be used in conjunction with vaccines. These drugs are part of a category called “small molecule targeted therapies” and some, such as lenalidomide, are already approved to treat certain cancers by the FDA. Lenalidomide has a very positive effect on the immune system – it stimulates T-cell production, increases NK cell potency, and suppresses cells that temper immune system function.

Cancer research has made tremendous progress, and the new technology being developed may soon enable doctors to treat the “untreatable.” By designing vaccines that work optimally with the immune system, cancer biologists will one day make it possible to destroy cancer while limiting damage to healthy tissue. Hopefully before long, being diagnosed with cancer will not be nearly as frightening as it is today, and we will have many dedicated researchers to thank.

References:
[1] Palena C. and Schlom J. “Vaccines Against Human Carcinomas: Strategies to Improve Antitumor Immune Responses.” Journal of Biomedicine and Biotechnology 2010:380697: [Epub 2010]. Web.