Cancer immunotherapy – redefining vaccines

Key text

Vaccines are taken for granted in developed countries; since mass immunisation was introduced in Australia in 1924, deaths from infectious diseases have now become a rare event. You may not even know what diseases like diphtheria, pertussis or smallpox are. Those dreaded jabs save around 3 million lives worldwide, every year.

Traditional vaccines were developed against antigens, foreign substances (on the surface of bacteria or viruses) that our immune system reacts to. Our immune system's reaction prepares the body to fight off any future infection by the same 'germ'. Unfortunately though, this type of vaccine can only be developed for diseases that are caused by bacteria or viruses.

Less than 20 per cent of cancers are caused by viruses, so making a vaccine for many cancers is not an easy task (Box 1: Guarding against viral cancer – Gardasil^®). For patients who already have cancer, current treatments include surgery, radiotherapy and/or chemotherapy, all of which have varying degrees of success and have limited room for improvement. The need for better treatment options is increasing, with cancer now the leading cause of death in Australia (28 per cent of all deaths).

Modern research into cancer vaccines stems from a radical experiment conducted over 100 years ago. In an experiment that would never be approved today, William Coley injected cancer patients with live bacteria. Amazingly, he found that some of his patients were cured. Coley didn't fully understand why his treatment worked; however, 'Coley's toxins', as they became known, showed scientists that immunisation could be used not only to prevent disease, but also to treat pre-existing disease.

But how can we possibly develop a vaccine against our own (diseased) cells? Fortunately, cancerous cells often have substances on their surface that are not present on other body cells. These antigenic substances could be used in cancer vaccines to stimulate our immune system to attack cancer cells. However, the differences between normal body cells and cancerous cells are not always obvious (Box 2: What is cancer?). Being body cells, cancer cells are good at hiding from our immune system. Research into cancer immunotherapy is aimed at helping the immune system find these hidden cells.

Homing in on cancer cells

Unlike traditional vaccines, cancer immunotherapy treats existing disease by targeting cancerous body cells. Coley's toxins are believed to have acted by generally stimulating the body's immune response. Although progressive at the time, his early version of immunotherapy was not specific to the patient's cancer cells so was not always effective. Today cancer immunotherapy has progressed to specifically target cancer cells.

Cancer immunotherapy can be broadly divided into two categories: active immunotherapy which stimulates the body's own immune response to cancer cells and passive immunotherapy which uses parts of the immune system created outside the body to fight cancer.

Tricking the body – active immunotherapy

Related site: The immune system – in more detail A clear overview of the role of different cells in the immune system. (Nobel Foundation, Sweden)

Can we trick the immune system into attacking our own diseased cells? Trials in Australia with vaccines containing antigens found on cancerous cells, have been encouraging. In a small Melbourne-based study, 19 melanoma patients were given a vaccine containing a cancer antigen combined with a substance that promotes the immune response. Two years later, 17 of the patients which were all initially at high risk of relapse were still alive.

A promising antigen that could be used in cancer vaccines is telomerase. Telomerase is an enzyme that makes cancer cells immortal and is absent from most normal cells. By finding the active parts of telomerase, researchers in Sydney have laid the foundation for developing a telomerase vaccine.

Unlike the 'one size fits all' approach of most vaccines, active immunotherapy often requires a vaccine tailored to the individual patient's cancer cells to be effective. Tailor-made vaccines are being researched in Australia using dendritic cells. These cells are like sentries that let the body know when there is an antigen present. They do this by collecting and presenting the antigen to the body's army of killer T-cells, which then recognise and attack anything with that antigen (such as a cancer cell). But dendritic cells don't always get the message through to T-cells in cancer patients. Australian research is aimed at giving dendritic cells a helping hand by culturing them outside the body with a patient's cancer cell antigen.

When used as a vaccine, these dendritic cells have resulted in complete remission in 15 per cent of melanoma patients.

Although they produce an immune response, being individually tailored for each patient, active immunotherapies can be expensive and time consuming. Another Australian trial is aimed at removing the need to treat dendritic cells outside the body. The vaccine Lipovaxin, combines cancer cell antigen with a substance that targets dendritic cells inside the body. Once it has combined with dendritic cells, they then present the antigen to T-cells which attack the cancer.

Despite promising results with active immunotherapy trials, vaccines tailored to a patient's cancer cell antigen can become less effective with time. This is because the antigen from any remaining cancer cells can change through mutation; vaccines have to then be redeveloped to target the changed antigen.

Magic bullets – passive immunotherapy

Related site: Monoclonal Antibody Production A graphic showing how monoclonal antibodies are produced using mouse cells. (Access Excellence, USA)

The guided missiles of medicine, monoclonal antibodies are antibodies that are created in the laboratory to home in on and destroy cancer cells. They are created to target a specific antigen in or on cancer cells, and can be made more lethal by being loaded with toxins, chemotherapy drugs or radioactive material. Monoclonal antibodies are produced by injecting mice with antigen; the B-cells produced in response by the mice are then fused with cancer cells. This makes the B-cells immortal allowing scientists to culture these specific antibody-producing cells indefinitely. The antibodies they produce are all identical and home in on the original cancer antigen.

Monoclonal antibodies, or mAbs as they have become affectionately known, are used to treat a range of cancers. Herceptin^® is a mAb that has been used successfully to treat breast cancer in Australia. It works by binding to and inactivating a protein (HER2) on the surface of cells that causes some types of breast cancer.

But mAbs aren't always the magic bullet we were promised when they were first discovered. Treatment can be expensive, needs to be repeated and has caused problems when patients' immune systems reject the foreign mouse-produced antibody. Genetic engineering to produce humanised versions (including Herceptin) have made mAbs a more attractive treatment option.

Vaccines are no longer a simple injection of inactive bacteria or viruses to prevent disease. Scientists are constantly finding new ways to train the immune system to target already diseased cells. Immunotherapy is redefining our understanding of vaccines.

Related Nova topics:

Immunisation – protecting our children from disease

Kissing the Epstein-Barr virus goodbye?

Sun and skin – a dangerous combination

Epigenetics – beyond genes

Box 1: Guarding against viral cancer – Gardasil^®

An example that would be familiar to many Australians is the vaccine Gardasil^®. In 2007 the Australian Government started a program to immunise all girls aged between 12 and 13 with Gardasil^®. This vaccine was developed to prevent cervical cancer, which is almost always caused by human papillomaviruses (HPVs). It protects against two HPV strains that are responsible for 70 per cent of cervical cancers.

Gardasil^® was developed using technology developed in Australia. In a breakthrough for the vaccine's development, Professor Ian Frazer (2006 Australian of the Year) and Dr Jian Zhou used gene technology to make virus-like particles which resemble HPV, but aren't infectious. When used in a vaccine, these virus-like particles are detected by our immune system which then produces antibodies against two HPV strains.

Trials with the vaccine have been pretty convincing. The drug company Merck showed Gardasil^® is 100 per cent effective at protecting (previously unexposed) people against HPV strains 16 and 18. But it is not a cure-all. Vaccinated people can still be infected by one of the many other strains of HPV, so regular Pap screening for cervical cancer is still necessary.

Gardasil^® is a prophylactic vaccine, that is, it prevents infection by HPV. Scientists are now working on developing therapeutic vaccines for women who have already been exposed to the virus.

Related sites

• Controlling cancer through immunisation – a glass half full? (Sir Mark Oliphant Conferences, Australia)

• Australian Broadcasting Corporation
  • Cancer vaccine (Behind the News, 5 September 2006)
  • Cervical cancer vaccine raises questions (ABC News in Science, 26 October 2005)

Box 2: What is cancer?

One common theme though, is that cancer cells develop from normal body cells that have become out of control. They don't respond normally to signals that control cell growth and death, and instruct cells to do specialised jobs. As a consequence, cancer cells divide more often than the normal body cells they came from, and die less often than new cells are made. This produces a growth or tumour. If tumour cells stay put, the tumour is described as benign, but if they also develop the ability to spread and invade other tissues in the body, a process called metastasis, the tumour becomes malignant, or a cancer.

What causes cancer cells to be out of control? The simple answer is damage to the cell's programming, held in the genes. There must be several changes to a cell's genes before they become able to make a tumour, and several more before the tumour becomes invasive. These changes can be caused by a range of factors, including exposure to UV light, X-rays, chemicals or viruses. Also, some people inherit gene variants that predispose them to particular cancers, which is why some cancers run in families.

The genetic changes which promote cancer commonly occur in genes that control normal cell growth and death. Two types of gene commonly damaged in cancer, are proto-oncogenes and tumour suppressor genes. These genes are often likened to the accelerator and brake in a car. Proto-oncogenes speed up cell growth when needed and tumour suppressor genes slow it down. But when either of these genes is changed, cell division can get out of control. For example, p53, also known as the 'guardian of the genome', acts as a tumour suppressor gene (the brakes of the cell). Scientists have found that p53 no longer functions properly (is mutated) in 40 per cent of all cancers.

DNA repair genes belong to another group of genes often damaged in cancer cells. These are like the mechanics of the cell, they look after the DNA, making repairs when it is damaged. If the repair genes mutate they may no longer be able to fix other cancer-causing mutations.

Related sites

• Understanding cancer (National Cancer Institute, USA)

• Cell biology and cancer (Learner.org, USA)

• DNA and genes (Back to basics, Australian Academy of Science)

• Cancer, genes and inherited predisposition overview (Centre for Genetics Education, NSW Government)

Activities

• US National Institutes of Health (USA)
  • Cancer and the cell cycle – students use resources to help explain how cancer develops.
  • Cancer as a multistep process – students use a simulation to test several hypotheses about the development of cancer.
  • The immune system and cancer vaccines – an interactive tutorial on the role of the immune system in treating cancer.

• Howard Hughes Medical Institute (USA)
  • Cancer: Animations – a series of animations about cancer.

• Cancer Quest (Emory University, USA)
  • Cancer treatment: The GRID! – a game in which students test their knowledge about a range of cancer treatments.

• The Curriculum Corporation (Australia)
  • Ian Frazer discusses the cervical cancer vaccine, 2008 – Ian Frazer discusses research that led to the development of the Gardasil vaccine. (Note: Access is restricted to Australian and New Zealand schools.)

• Cold Spring Harbour Laboratory (USA)
  • Inside cancer: Multimedia guide to cancer biology – a series of animations that describe aspects of cancer. Includes the sections 'Hallmarks of cancer', 'Causes and prevention', 'Diagnosis and treatment' and 'Pathways to cancer'.

Activity 1. Cancer immunotherapy

• Form into a group of 4 students (this is your 'home group')

• Each member of your group will be given one of the following aspects of cancer immunotherapy to research:
  1. Immunotherapy using telomerase
  2. Immunotherapy using cultured dendritic cells
  3. Immunotherapy using monoclonal antibodies
  4. Production of monoclonal antibodies

• The students with the same topic from different groups are then to come together to complete the research task. This is your 'expert group'

• Using the information on this website and the links under the useful sites tab, you should:
  • explain whether the immunotherapy is active or passive
  • describe in a series of dot points how the therapy works in terms of the immune system and how it targets cancer cells
  • give an example of research involving this particular immunotherapy
  • evaluate this type of immunotherapy for treating cancer
  • ensure each expert group member has a copy of the information gathered

• Students are then to return to their home groups and take turns teaching their group about each particular type of immunotherapy.

• Each home group then produces a poster with diagrams summarising the four aspects of immunotherapy.

Further reading

Useful sites

Explains immunotherapy and its use for treating cancer.
http://sarcomahelp.org/learning_center/articles/immunotherapy.html

Understanding cancer series: The immune system (US National Institutes of Health, USA)

Presents a series of graphics to help understand cancer, including cancer immunotherapy.
http://www.cancer.gov/cancertopics/understandingcancer/immunesystem

Immunotherapy (American Cancer Society)

Clearly explains the immune system and types of immunotherapy for cancer.
http://www.cancer.org/docroot/ETO/eto_1_3_Immunotherapy.asp

Immunotherapy cancer treatment (Cancer Supportive Care, USA)

Provides an overview of cancer immunotherapy.
http://www.cancersupportivecare.com/immunotherapy.html

Using the immune response to attack tumors (National Center for Biotechnology Information, USA)

Provides information on using immunotherapy to treat cancer.
http://www.ncbi.nlm.nih.gov/books/bv.fcgi?highlight=immunotherapy&rid=imm.section.2184

Queensland Institute of Medical Research

• Cancer immunotherapy
  Describes Australian research into cancer immunotherapy
  http://www.qimr.edu.au/research/labs/chriss/index.html

• Dendritic cells and cancer
  Describes Australian research into the use of dendritic cells for treatment of cancer.
  http://www.qimr.edu.au/research/labs/alejl/index.html

Australian Broadcasting Corporation

• Research into telomerase (The Health Report, 2 April 2007)
  Discusses Australian research into the structure of telomerase.
  http://www.abc.net.au/rn/healthreport/stories/2007/1888419.htm

• Smart drugs (Catalyst, 26 October 2006)
  Discusses the use of monoclonal antibodies in Australia.
  http://www.abc.net.au/catalyst/stories/s1774083.htm

• Cancer vaccine (Catalyst, 14 October 2004)
  Reports on Australian cases of successful immunotherapy.
  http://www.abc.net.au/catalyst/stories/s1220020.htm

Facts and figures (Cancer Council Australia)

Provides general information and statistics on cancer in Australia.
http://www.cancer.org.au/aboutcancer/FactsFigures.htm

Monoclonal antibody technology – the basics (Access Excellence, USA)

Gives a clear overview of monoclonal antibodies.
http://www.accessexcellence.org/RC/AB/BC/Monoclonal_Antibody.php

Glossary

antigen. Any foreign substance, usually a protein, that stimulates the body's immune system to produce antibodies. (The name antigen reflects its role in stimulating an immune response – antibody generating.)

bacterium (plural bacteria). A single-celled, microscopic organism without a distinct nucleus.

B-cells (B-lymphocytes). A type of white blood cell that originates and develops in the bone marrow. B-cells can be stimulated to produce antibodies.

chemotherapy. Treatment of disease by using chemical compounds. Cancers are commonly treated by administering chemicals that are toxic to malignant cells.

dendritic cell. A cell that is involved in regulation of the immune system. Dendritic cells act by consuming and presenting antigen to lymphocytes. This activates the lymphocytes to fight infection or disease.

immune system. The cells, tissues and organs that assist the body to resist infection and disease by producing antibodies and/or altered cells that inhibit the multiplication of the infectious agent and provide resistance to disease.

immunotherapy. The use of the immune system to treat existing disease. This can be either through active immunotherapy, in which the patient's own immune system is trained to recognise diseased cells to be destroyed, or through the passive immunotherapy in which diseased cells are destroyed by antibodies created outside the body.

metastasis. The movement of cancer cells from one location to another part of the body, usually via the blood or lymphatic system.

monoclonal antibodies (mAbs). Artificially created, identical antibodies that can be used to treat disease. mAbs will only bind to one antigen. They are created by fusing antibody-producing B-lymphocytes with immortal cancer cells.

mutation. A change in the DNA sequence of a gene that may be harmful or beneficial. It is the only process that actually leads to new forms of a gene, and it is the ultimate source of all variation.

radiotherapy. The use of high energy radiation to treat cancerous cells. The radiation destroys or slows the abnormal cells.

T-cell. White blood cells that are important for the body's immune response to specific antigens. Killer T-cells are like soldiers who search out and destroy invading bacteria or viruses or cancer cells.

toxins. Substances, produced by microorganisms, which affect the functioning of another organism.

virus. A submicroscopic infectious agent consisting of a nucleic acid (DNA or RNA) molecule surrounded by a protein coat. Viruses cannot replicate outside a living cell. More information can be found at How viruses work (How Stuff Works, USA).