Interesting video about HER2

This looks like an advert but it’s interesting none the less:

I found it at BREASTCANCER.ORG and it was created by Genentech BioOncology. Yes, Genentech make money from Herceptin.

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TED Talks on Cancer

I teach on a Cancer Biology module. In preparing for my lectures, I have been checking out some of the information on the internet about cancer. I started with TED talks because the talks are bit sized pieces aimed at an general audience.

TED talks have curated a playlist entitled: A cure for cancer? So far I have checked out three of the five talks and they are interesting. The talks are 20 min in length and deal with the importance of microenvironment, angiogenesis and a multi-disciplinary approach to cancer research.

I don’t agree with everything they say. I particularly didn’t like when William Li started to talk about anti-angiogenic foods. However, I appreciate the importance of a good diet with fruit and vegtables. Linking this to just angiogenesis, I am not so sure….

This afternoon, I will talk about the role of infections in cancer. The best example, in humans is HPV. TED Talks has an interesting talk about an infectious cancer affecting the Tasmanian devil.

As of today, there are 18 TED talks tagged ‘Cancer’. I haven’t watched them all. A little while ago, I checked out Ivan Oransky: Are we over-medicalized? It’s an nice counter point to some of the science and medicine talks.

For more information, maybe check out some of my other posts:

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Fundamentals of Immunology

Fundamentals of Immunology

As part of the Interactive Immunology SSC offered to the Medical Undergraduates, I give a flip chart review of immunology. I try to keep it lively with lots of interaction with the students, a few stories and some hand drawn pictures. Together, we usually do a good job of reminding ourselves about the fundamentals of immunology.

We cover four key themes:

  1. Concepts
  2. Cells
  3. Molecules
  4. Pathology and therapeutics

I begin by asking the students about some terms they have learned over the previous weeks – basic, fundamental terms. Very quickly, they say “Innate” and “Adaptive”. This is how, conceptually, we divide the immune system. We then discuss the differences between these two parts of the immune system, some of the cells and key processes that facilitate immunity.  Examples of what I discuss is shown in this table:

Innate Immune System Adaptive Immune System
Concepts
Speed of response Minutes and Hours Days and weeks
Specificity of response Pattern recognition receptors Very specific peptides(8-10 amino acids in length)
Immunological memory Not really Yes, a key element of adaptive immunity
Cells Neutrophils B-cells
Macrophages Helper T-cells
Monocytes Cytotoxic T-cells
Endothelial cells
Molecules Proinflammatory cytokines – TNF Antibodies and immunoglobulins
Adhesion molecules – E-selection Helper cytokines – IL-12
Chemokines – CXCL8 (IL-8) Proliferation cytokines – IL-2, IL-4
Pathology and therapeutics Auto-immunity – when inflammation goes wrong Vaccination – measure antibody responses. Examples: smallpox and Hepatitis vaccines
Anti-TNF therapeutics Immunosuppression to facilitate transplantation
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A useful ‘poke in the eye’…

Finding myself over the age of 40 means I should start taking better care of myself. In honesty, my body keeps telling me that I should take care of myself. One of the things I have tried to do is have an annual eye check. During my check up last year, I ended up discussing anti-cytokine therapeutics with the optician.

My optician is in fact an optometristMr Chris Ellis at RN Roberts Ltd. He told me that wet age related macular degeneration can cause vision loss in as little as two weeks and regularly takes just a few months. There is a sad story about the impact of vision loss at the AMD Alliance website. What’s poignant is that people who have AMD in one eye have a very high chance of getting AMD in the other eye. This is probably because AMD should be regarded as a systemic disease rather than just a disease of the eye. Without therapeutics, this meant that optometrists could only watch while their patients lost their central vision.

The outlook for wet AMD is now much better following the discovery of vascular endothelial growth factor (VEGF) and development of anti VEGF agents. Wet AMD is the result of growth of blood vessels at the back of the eye. The blood vessels damage the cells in the eye that allow us to see – the rods and the cones. Blood vessel growth is caused by the cytokine, VEGF. Antibodies which block VEGF are injected into the eye of patients with AMD and it can halt vision loss and improve sight in some patients [1].

The Lasker Foundation awarded their Clinical Medical Research Award for 2010 to Dr Napoleone Ferrara for the discovery of VEGF and the development of anti-VEGF therapy for wet macular degeneration. There is a nice history of the discovery on the Lasker Foundation website. What’s interesting is that VEGF was first purified and cloned in 1989. Over the following 10 years, while working at Genentech, Dr Ferrara developed an antibody against VEGF and tested it in animal models. During 2000, clinical trials started in AMD with the anti-VEGF antibody (references below).

In 2006, the FDA approved the use of ranibizumab (Lucentis®) for the treatment of wet AMD. The European Commission approved it on 22 January 2007. This shows how long drug development takes – seventeen years from the discovery of the gene and six years in clinical trials before the agent can be approved for use. Science2therapy is a patient business…

Selected sources:

A summary of the European public assessment report for Lucentis.   http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/000715/WC500043548.pdf

The papers describing the purification and cloning of VEGF

Ferrara, N., Henzel, W.J. “Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells” (1989) Biochemical and Biophysical Research Communications 161:851-858 Pubmed

Leung, D.W., Cachianes, G., Kuang, W.-J., Goeddel, D.V., Ferrara, N. “Vascular endothelial growth factor is a secreted angiogenic mitogen”   (1989)  Science 246:1306-1309 Pubmed

The reports on the clinical trials (Free access)

Rosenfeld, P.J. et al. Ranibizumab for neovascular age-related macular degeneration. N. Engl. J. Med. 355, 1419–1431 (2006).

Brown, D.M. et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N. Engl. J. Med. 355, 1432–1444 (2006).

An interview with Napoleone Ferrara in the International Journal of Developmental Biology

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Antibodies are cool!

The Biochemical Society is 100 years old this year. To celebrate, they have prepared a list of the most important discoveries. Like lists of the best books or the best films, the joy is not in the result but in the discussion. In their “what did we miss section”, I added antibodies. I love antibodies. Well actually that’s probably over stating the case a bit, but I think antibodies are cool. Remember, I am a nerd so it’s OK for me to think that molecules are cool.

Why do I think antibodies are cool?

Well firstly, they help to keep you, me, and our families, alive. Antibodies are proteins made by our white blood cells that bind bacterias and viruses and help us to clear them from our bodies. Most vaccines depend on a good antibody response to work. In order to measure my vaccination against hepatitis, my antibody levels were measured.

Secondly, antibodies are some of the most sensitive things in the world. After they are made, antibodies undergo a process called “affinity maturation”. This basically means they get better and better. This sensitivity is caused by small changes in the DNA that makes the antibody and then a test for the strength of the antibody to the virus. The good antibodies are encouraged the poor ones ignored….

Thirdly, antibodies are incredibly specific. They typically recognise just 8 to 10 amino acids. This means a chain of about 30 carbon and nitrogen molecules. If you change even the order these amino acids, the antibodies don’t work any more. This specificity is also remembered. So your antibodies remember a small peptide sequence from a virus they met years ago.

The combination of specificity and sensitivity makes antibodies very useful in the laboratory. They are used for clinical diagnosis and for cutting edge research. Using an antibody we can detect very small amounts of proteins on the surface of cells. As was lyrically described during a collaboration with an artist and a poet, we use them to “seed our cells with light”.

Finally, as if all that wasn’t enough, antibodies are a great example of science2therapy. I have described herceptin previously. Herceptin is an antibody against a growth factor receptor that is used to treat breast cancer. The first antibody to really make a difference to clinical treatment was ritiximab, an antibody against a B-cell molecule called CD20. Rutiximab is now routinely used for the treatment of Non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia.

The usefulness of antibodies in the clinic is prompting the development of many different antibodies. They are useful for targeting molecules on the surface of cells. An interesting Perspective article from Nature Drugs Discovery (payment required), showed a graph with an exponential growth of the number of antibodies in clinical development.

For me, antibodies are a science2therapy example of how science has already delivered, continues to deliver and will continue to deliver in the future. Optimistic days for a cool little molecule that inside all of us :-)

A few interesting facts:

Antibodies are small (about 12 nanometers). There is a very nice graphic here about scale.

In 1984, the Nobel Prize in Physiology or Medicine was awarded jointly to Niels K. Jerne, Georges J.F. Köhler and César Milstein “for theories concerning the specificity in development and control of the immune system and the discovery of the principle for production of monoclonal antibodies”.

Last year, the US market spent $2.2 billion on Rituxin, the brand name for rituximab, according to this report by the IMS Institute for Healthcare Informatics.

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Inspiring Scottish Cell Therapy

Last week, I had the opportunity to listen to and meet Professor Dorothy Crawford. Following an invitation to give a public lecture, Professor Crawford agreed to give, not one, but two lectures – one for the public and one aimed towards a scientific audience. The public lecture was based on her book entitled Deadly Companions: How microbes shaped our history. The scientific lecture was based on how she successfully moved science, particularly immunology, to a cellular therapy.

I have read about Professor Crawford’s pioneering work on cytotoxic T-cell therapy for treating Epstein-Barr virus associated condition entitled post-transplant proliferative disease (references below). Eptein-Barr virus has a special place in my heart because it knows secrets that I am still trying to understand fully – how to immortalise a human B-cell. It is the ability of the virus to immortalise B-cells that causes this post-transplant lymphoma. In order to prevent rejection, patients are immunosuppressed. The immunsuppression allows the outgrowth of Epstein-Barr virus immortalised B-cells which is post tranplant proliferative disease.

Normally the virally immortalised B-cells are controlled by the immune system. Cytotoxic T-cells kill the virally infected cells. This keeps the virus under control in healthy people who have the virus. Most people, including me, live happily with Epstein-Barr virus.

Inspired by this science, which she helped discover, Professor Crawford developed cytotoxic T-cells which could be given to a patient who had an outgrowth of these Epstein-Barr virus immortalised cells. With her team, she developed a bank of these cells, which could be matched to an individual patient and administered safely. These cells were used, in a clinical trail, to treat 33 patients all of whom had progressive disease despite conventional treatment. Their prognosis was poor.

The happy and inspiring result of this trail was that over half of the patients showed a response to the cells and none of the patients showed adverse responses to this novel treatment.

For me, it is inspiring that this was not a custom designed cell from an individual but a bank of cells from helpful blood donors that were tailored to help patients. The approach was based on sound science, it was clever and it was world leading. A new bank of cells that will be capable of supplying cells worldwide is currently being established in Scotland. It is a very worthy next step following this successful trail.

References:

Haque T, McAulay KA, Kelly D, Crawford DH. Allogeneic T-cell therapy for Epstein-Barr virus-positive posttransplant lymphoproliferative disease: long-term follow-up. Transplantation. 2010; 90:93-4.

Haque T, Wilkie GM, Jones MM, Higgins CD, Urquhart G, Wingate P, Burns D, McAulay K, Turner M, Bellamy C, Amlot PL, Kelly D, MacGilchrist A, Gandhi MK, Swerdlow AJ, Crawford DH. Allogeneic cytotoxic T-cell therapy for EBV positive posttransplantation lymphoproliferative disease: results of a phase 2 multicenter clinical trial. Blood. 2007 Aug 15;110(4):1123-31. Epub 2007 Apr 27. PubMed PMID: 17468341.

Wynn RF, Arkwright PD, Haque T, Gharib MI, Wilkie G, Morton-Jones M, Crawford DH. Treatment of Epstein-Barr-virus-associated primary CNS B cell lymphoma with allogeneic T-cell immunotherapy and stem-cell transplantation. Lancet Oncol. 2005 May;6(5):344-6.

Wilkie GM, Taylor C, Jones MM, Burns DM, Turner M, Kilpatrick D, Amlot PL, Crawford DH, Haque T. Establishment and characterization of a bank of cytotoxic T lymphocytes for immunotherapy of epstein-barr virus-associated diseases. J Immunother. 2004 Jul-Aug;27(4):309-16.

Haque T, Wilkie GM, Taylor C, Amlot PL, Murad P, Iley A, Dombagoda D, Britton KM, Swerdlow AJ, Crawford DH. Treatment of Epstein-Barr-virus-positive post-transplantation lymphoproliferative disease with partly HLA-matched allogeneic cytotoxic T cells. Lancet. 2002 Aug 10;360(9331):436-42.

Haque T, Taylor C, Wilkie GM, Murad P, Amlot PL, Beath S, McKiernan PJ, Crawford DH. Complete regression of posttransplant lymphoproliferative disease using partially HLA-matched Epstein Barr virus-specific cytotoxic T cells. Transplantation. 2001 Oct 27;72(8):1399-402.

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Interferons – antiviral cytokines used to treat viral hepatitis

A few weeks ago, I prepared a lecture for my Cytokine Therapeutics module about interferons, anti-viral cytokines. A soluble antiviral activity was described by two virologists, scientists working on viruses, Issacs and Lindenmann in 1957. It took twenty years of research but this activity was characterized as a family of proteins called interferons. Interferons interfere with virus infection. They act on cells to make them less suitable for virus growth and more likely to be detected by cytotoxic T-cells that kill virally infected cells.

Inteferons inhibit virus growth by inhibiting the proliferation of virally infected cells. In fact, they inhibit the proliferation of all mammalian cells. For this reason, interferons were first used as a therapeutic in cancer and showed some promise in leukaemia. However, they did not offer a real cure and often cause flu like symptoms.

The cloning of the interferon genes allowed the generation of a pure form of the proteins. One of the family, interferon alpha, is now used as a therapy for hepatitis C virus (HCV). This is intellectually satisfying – an antiviral protein discovered by humans from humans and now used by humans to augment antiviral activity in humans.

To treat HCV, interferon is combined with an antiviral drug, ribavirin. This is currently standard therapy recommended by NICE. The interferon is pegylated – a modification that makes it last longer in humans. This means that less doses have to be taken. The side effects are a challenge and the treatment takes many months but is successful in about 50% of patients. Not just science2therapy but often science to cure :-)

References:

Ernest C. Borden, Ganes C. Sen, Gilles Uze, Robert H. Silverman, Richard M. Ransohoff, Graham R. Foster and George R. Stark Nature Reviews Drug Discovery 6:975-99  (doi:10.1038/nrd2422) (may need payment subscription)

 

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