New Cancer Research at University of Miami

Doctors at the University of Miami have claimed a breakthrough in cancer treatment, using the immune system to attack small, metastatic tumors. After surgical tumor removal, metastasis of small tumors can become lethal for the patient. While large tumors can be identified and treated (with surgical removal or radiation), small tumors are difficult to identify, especially if they spread to unknown or inaccessible areas of the body.

These small tumors are unaffected by the body's immune system because they lack the antigens needed to initiate an immune response. Dr.Eli Gilboa and his UM team are researching DNA and RNA manipulation to induce expression and production of antigens on cancerous tumors. This research is currently being conducted in rat trials, and will require much more extensive time and research for human treatment. A particular challenge is the observation of immune tolerance to tumor antigens.

Article sources: http://www.miamiherald.com/2010/05/18/1634230/um-developing-potent-weapon-against.html#Comments_Container

Image source: http://repairstemcell.files.wordpress.com/2009/05/breast-cancer-cell2.jpg

Biotechnology: New wave at Pfizer

Pfizer is currently investing into new biotechnological solutions for improvements of existing drugs. Rather than contain synthetically created chemical compounds, "biologics" derive their materials from living cells. Rather than create new drugs with the technology, companies like Pfizer and Merck plan to create similar versions of the drugs but sell them at lower costs.

While the compounds are generally far away from reaching the market, the article elucidates a whole new field of rival drugs from companies hoping to give more efficient, effective care by tapping into biotechnological techniques.

Source: http://online.wsj.com/article/SB10001424052748704464704575208580328253618.html?mod=rss_whats_news_us

Death of Smallpox = Birth of HIV

Researchers currently hypothesize a possible link between the gradual decline in use of the smallpox vaccination after eradication and the sudden rise in cases of HIV in Africa. After taking the white blood cells from individuals recently vaccinated by smallpox and examining their behavior in response to HIV, they found that HIV replication rates were five times lower than in normal white blood cells. Hence, they hypothesize that the smallpox eradication efforts may have had a role in stemming the rise of HIV in Africa for decades.

A potential explanation for this finding is the possibility that smallpox-inoculated individuals have long-term impacts on their immune system, such as lower rates of the CCR5 expression necessary for the spread of HIV.

While it's too early to call the smallpox vaccine a true answer to our HIV problems, the research provides further evidence in the role of receptors in the spread of the notoriously debilitating illness.

Source: http://news.bbc.co.uk/2/hi/health/8686750.stm

Locking up malaria in your red blood cells...?!

Researchers at the Harvard School of Public Health recently stumbled upon a protein that allows Plasmodium falciparum malaria cells to exit infected red blood cells and further spread throughout the body. They originally thought that the protein functioned in allowing malaria to enter the cell, but they were surprised when eliminating the protein seemed to prevent malaria from exiting red blood cells.

During a typical infection, mosquitoes inject malaria parasites into a victim. The parasites migrate to the liver, where they slowly grow until they begin to spread to red blood cells weeks later. At this point, symptoms should begin to surface. Staying outside of the cell too long will result in the death of the malaria cell by the natural human immune system, so right after the cell ruptures, mature cells tends to enter another RBC as quickly as possible. Without the necessary protein kinase, malarial cells still develop as normal, but they just don't have a way to exit the cell and further infect the body. The protein doesn't seem to exist naturally in humans, suggesting that it's removal shouldn't have any toxic effects.

Researchers hope that this line of research can lead to antimalarial treatments that can contain an existing infection. Also, because the method allows for mature malaria to survive within the cell, it provides mature invasive parasites for study in vaccines, a rarity in immunology.

http://www.sciencedaily.com/releases/2010/05/100514171912.htm

Stem Cell Transplantation Solves Mystery Illness

Katie Pulling spent the majority of her years suffering from an illness with a wide variety of symptoms no doctor could diagnose. Medical professionals tried TONS of treatments to no avail in abating her symptoms. However, the solution finally came when she contracted a severe case of fulminant infectious mononucleosis (FIM), a rare disease that appeared to somehow be linked to all of her other illnesses. Doctors suspected that her immune system was not reacting to the disorders properly, leading to a ton of unclear symptoms.

The final solution was to replace her current immune cells with transplanted stem cells. The procedure was dangerous, but the results fixed her immune system, further emphasizing the potential for experimental stem cell transplants as a means of curing illness, even those that baffle the best of doctors.

Source: http://www.sciencedaily.com/releases/2010/05/100517091827.htm

Provenge: Is it Worth It?

There is a huge debate currently revolving around whether Provenge is worth its cost. Each infusion of Provenge will cost $31,000, bringing the full cost of the treatment for three infusions to $93,000. According to the Phase III study, the drug extends life by an average of 4.1 months, bringing the cost to about $23,000 per month of life extension.

The cost stems from the fact that every dose is unique to each patient. As I mentioned in my previous post, the treatment is composed of GM-CSF treated ex-vivo loaded dendritic cells, meaning that dendritic cells are extracted from a patient, loaded with the prostate cancer specific epitope, and treated with a GM-CSF fusion protein to help the dentritic cells to mature to improve their effectiveness at presenting antigen to T-cells. Dendreon spent close to 1 billion dollars as well as 15 years developing this immunotherapy, and is still developing three manufacturing facilities in Los Angeles, Atlanta and New Jersey for the production of this drug. Should Provenge have been approved by the FDA if it only extends a patient’s life by 4 months for a cost close to $100,000?

In my opinion, yes. During late stage prostate cancer, very few patients want to receive chemotherapy, which has many side effects and a similar prognosis in relation to the extension of life. Provenge, has very few side effects because it takes advantage of the body’s natural processes. More importantly, this approval will pave the way for other active immunotherapies and will help to jumpstart a field with incredible potential for cancer treatment. The specific debate over whether Provenge is worth the cost is difficult to answer; however, the approval of this drug was a huge step in the advancement of cancer therapeutics.

Jonathan

Sources:
Antonarakis, E.S.; Drake, C.G. “Current status of immunological therapies for prostate cancer”. Curr Opin Urol. 2010, 20, 241-246.

http://www.cnn.com/2010/HEALTH/04/27/provenge.prostate.cancer.fda/index.html

Additional Reading Summary, Week 7

Sorry for the late post. There were so many articles that it took a little longer than expected. Here is my summary of the articles.

“The T-lymphocyte antigen receptor—paradigm lost”
Jens Jensenius and Alan Williams

This article speaks about the ongoing paradigm shift from the idea T-cells were essentially the same as membrane bound antibodies. It was thought for quite some time that if the T-cell receptor was so similar to the immunoglobulin, identifying structures with V-domains on T-lymphocytes would allow scientists to identify the receptor. The article talks about why this paradigm should be shifted due to the disparity between immunoglobulin and the T-cell receptor. For example, the T-cell receptor is unable to directly bind unprocessed antigen. In addition, the receptor’s co-recognition of the histocompatibility complex along with foreign antigen indicates the necessity for the paradigm shift away from a foundation on immunoglobulin.


“On the Trail of the T-cell Receptor”
Mark Davis

Dr. Davis provides a great summary of the work that he and his lab did to be the first to clone the T-cell receptor. He gives a brief history of T-cells and the many theories that were proposed in regards to the receptor, such as the two receptor model, in which one receptor recognized antigen and the other the MHC. Dr. Davis recounts his decision to work on the T-cell receptor, a looming unknown in immunology, by applying what he knew best from CalTech, Cot curves and subtractive hybridization. Luckily, he determined that there was only a 2% difference between the B-cells and T-cells (approximately 100-200 genes). Therefore, using a library of cDNA probes to screen the B and T-cell libraries, the gene was finally narrowed down using the last clone, TM-86. Dr. Davis then moved to Stanford from the NIH to continue the research, and the process kicked into full gear. Once he presented the results at an immunology conference in Tokyo, the subject exploded, with countless other researchers desperately working to find the other chains of the receptor. Ultimately, Dr. Davis gives gave a great personal review of the process that went into discovering the T-cell receptor and the “breaching a major bottleneck in the understanding of the mechanism of the T-cell.”


“Isolation of cDNA clones encoding T cell-specific membrane-associated proteins”
Mark Davis, et al.
“Sequence relationships between putative T-cell receptor polypeptides and immunoglobulins”
Mark Davis, et al.


These two articles summarize the findings of Dr. Davis and his lab in more detail. The first article entitled, “Isolation of cDNA…” was the first paper to hint that the T-cell receptor gene had been found. Dr. Davis and his lab had determined that one of the cloned DNA copies of mRNA expressed only in T-cells, which was also a membrane bound protein, also hybridized in a region of the genome known to rearrange in T-cell lymphomas and hybridomas. These factors all indicated that this gene did in fact code for the surface T-cell receptor.

The second article recounts the comparison of this T-cell specific cDNA with cross-reacting cDNA clones from a thymocyte library. Their subsequent reactivity indicated that a variable, constant, and joining region were present within the gene segment and were very similar to those segments found in immunoglobulin proteins. Somatic rearrangement had already been observed, and further supported that this isolated gene segment encoded one of the chains of the T-cell receptor.