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.

A Description of Celiac Disease and How to Protect Children

I have a family member who suffered from this disease for a long time until he found out what was wrong. Now he eats a gluten-free diet and is feeling great – shout out to him! I though it would be nice to write about this disease because it might help any parents out there make smart choices for their babies. So without further ado, here you have my first post:

Celiac disease (CD) is a permanent auto-immune disease that occurs in some genetically predisposed individuals when they ingest gluten, a protein found in the grains wheat, rye, and barley. When individuals suffering from CD ingest gluten, their immune system attacks their intestines and causes lesions. Sufferers of the disease experience gastrointestinal symptoms such as abdominal pain, diarrhea, flatulence, and constipation. The damage done to the intestines often leads to the inability to properly absorb nutrients, which causes other symptoms such as anemia, weight loss, and osteoporosis.¹

To understand the mechanisms that cause CD and how it is diagnosed, it helps to understand some relevant microbiology. The major histocompatibility complex (MHC) is a part of our genome that allows our immune system to function properly. Within the MHC, there are human leukocyte antigen (HLA) genes which are used to synthesize specific proteins. The proteins made using these HLA genes are located on the outermost surface of our cells, the cell membrane. They are used to display markers that our immune system recognizes as belonging to our own healthy cells. These markers are called “self” antigens. When our immune system recognizes self antigens, it does no harm to the cells displaying them. However, when a cell is infected by a harmful microorganism, the proteins made using HLA genes allow the cell to display pieces of that microorganism on the cell membrane. These “non-self” antigens prompt the immune system to kill the microorganism within the infected cell, and the infected cell itself is consequently killed as a sort of collateral damage.

Expression of HLA genes varies tremendously within the human population, and the proteins produced using HLA genes are unique to every individual. There are two specific HLA genes that predispose people for CD: DQ2 and DQ8.⁴ Only one of these genes needs to be expressed for an individual to be predisposed to CD. From these genes, cells produce proteins which can display gluten to the immune system. Of course, gluten is not a naturally occurring protein within our bodies, so the immune system will recognize it as non-self and attack the cells (specifically, the intestinal cells).

Here's an animation I made for the visual learners out there...



When a person ingests food, the food moves from the mouth into the esophagus. No digestion or absorption takes place as the food passes quickly through the esophagus into the stomach. The stomach, used for digesting and churning food, is a very strong, muscular organ with relatively thick walls. Almost no nutrients get absorbed into the body through the stomach. After exiting the stomach, the partially digested food enters the duodenum, the uppermost section of our intestines where nutrient absorption begins. In a person with active HLA DQ2 or DQ8 genes, ingested gluten can be absorbed and presented to the immune system, causing damage to the intestines as described above.

Thus, three sources of evidence for diagnosing CD are:
1) Considering of the patients’ symptoms
2) Testing patients for the expression of HLA DQ2 and DQ8
3) Using a biopsy of the duodenum to check for damage to the intestines

As it turns out, however, only 4% of patients who express either the DQ2 or DQ8 gene actually develop CD.³ Scientists believe this is because there are additional genetic and environmental factors necessary for the disease to manifest itself. There are currently about 7 other genes being examined for the role they play in CD development.

Two possible environmental factors that might play a role in the development of the disease are the timing of gluten introduction to the diet and breast feeding patterns. One study, known as the DAISY experiment, suggests that 4-6 months of age is the optimal window of time to first feed a child food containing gluten so as to decrease the child’s chance of suffering from CD later in life.³ However, this study does not address the amount of gluten the child should be fed. Another study took on this issue and found that during an era when children were fed food containing high levels of gluten during weaning, 4 times as many children developed CD compared to past incidence.² Additionally, multiple studies support the notion that breastfeeding, particularly at the time of gluten introduction to the diet, significantly reduces a child’s chance of developing CD.³

The only known effective treatment for the disease is the complete avoidance of food containing gluten. Current research is aimed at using food grade enzymes to break down accidentally ingested gluten,⁵ and additional research may lead to the ability to use gene therapy to combat the negative effects that the expression of DQ2 and DQ8 facilitate. Until another treatment (or cure) is found, CD patients should avoid products made with wheat, rye, and barley, and parents should introduce gluten slowly into their child’s diet at 4-6 months of age, while the child’s mother continues to breastfeed him or her.

Thanks for reading, and if you have any questions, don’t be shy about asking me! I’ll do my best to help get them answered.

References:
[1] Gray AM and Papanicolas IN. “Impact of symptoms on quality of life before and after diagnosis of coeliac disease: results from a UK population survey.” BMC Health Services Research 10.105 (2010): [Epub ahead of print]. Web.

[2] Olsson C, Hernell O, Hörnell A, Lönnberg G, Ivarsson A. “Difference in celiac disease risk between Swedish birth cohorts suggests an opportunity for primary prevention.” Pediatrics 122.3 (2008): 528-534. Web.

[3] Silano M, Agostoni C, and Guandalini S. "Effect of the Timing of Gluten Introduction on the Development of Celiac Disease." World Journal of Gastroenterology 16.16 (2010): 1939-942. Web.

[4] Verdu EF, Huang X, Natividad J, Lu J, Blennerhassett PA, David CS, McKay DM, Murray JA. “Gliadin-Dependent Neuromuscular and Epithelial Secretory Responses in Gluten-Sensitive HLA-DQ8 Transgenic Mice.” AJP - Gastrointestinal and Liver Physiology 294.1 (2008): G217-225. Web.

[5] Ehren J, Morón B, Martin E, Bethune MT, Gray GM, Khosla C. “A food-grade enzyme preparation with modest gluten detoxification properties.” PLoS One 4:7 (2009): e6313. Web.