Ongoing Research

Research and New Therapies for Melanoma - Update August 2008

For reasons that are not entirely clear, melanoma has proven to be responsive to therapies involving the immune system. These therapies are termed immunotherapy and tend to focus upon the use of biological agents (substances or materials generally found within the body) that can stimulate the patients’ immune system to recognise and eradicate the tumour. To date, the most common form of immunotherapy involves the use of cytokines such as interferons, which are produced in very small levels within the body but are used at higher doses in order to stimulate the tumour fighting capacity of the immune system. Further therapies based upon stimulating the patients’ own immune system are at various stages of development. Examples include cancer vaccines and other cytokines such as interleukin-2.

An alternative approach that has been explored involves the infusion of tumour specific immune cells into the patient’s blood system. Once in the patients’ bloodstream, these cells travel around the patient’s body and eventually arrive at the site of tumour where it is hoped that they recognise and challenge the tumour. This approach is termed adoptive cell therapy and has generally involved the use of T-cells isolated from the patient. T-cells are important members of the immune system playing a pivotal role in protecting against harmful pathogens such as viruses. T-cells are generated in the bone marrow before being matured in the thymus and released to patrol the body within the blood and lymphatic system. T-cells can move into sites of infection within tissues where they either kill infected cells or produce cytokines that can further amplify the immune response. The combination of these properties makes T-cells highly attractive as a cancer therapy since they can patrol the body and specifically home into tumours.

The development of T-cells as an adoptive cell therapy for melanoma has been largely driven by researchers under the leadership of Dr Steven Rosenberg at the Surgery Branch of the National Institutes of Health, Washington, DC. Over an extended period of time, this group has carried out a series of trials examining the potency of adoptively transferred T-cells with recent reports documenting some highly encouraging clinical responses driven by T-cells against melanoma.  Other clinical research groups within the United States are also actively pursing translational studies focused upon the development of adoptive cellular therapies for melanoma. Our aim here in Manchester is to develop the technology and facilities in order to drive our research and to pursue trials of adoptive T-cell therapies for melanoma and other potential cancer targets.

The Basis of Adoptive T-cell Therapy

The initial problem concerning T-cell therapies is where to source the T-cells. T-cells have been isolated from both blood and tumour biopsies and subsequently cultured in the laboratory to achieve numbers which are suitable for clinical use. The use of T-cells derived from tumour (Tumour Infiltrating Lymphocytes – TIL’s) has proven effective in challenging the growth of melanoma. Reasons for this may include the expanded T cells maintaining several of the characteristics that caused them to migrate to the tumour in the first place. Protocols to isolate and expand the TIL’s have been optimised in Dr Rosenberg’s laboratory and are currently being replicated within the Christie Hospital. Once characterised and expanded, the TIL’s are re-infused into the patient generally after the patients have had their own white cells temporarily depleted by the use of chemotherapy. This is important since the absence of competing immune cells, including T-cells, appears to allow the tumour specific T cells to engraft and function more effectively. In order to aid the survival of the T cells, cytokines such as interleukin-2 may also be given.

The process though is technically demanding and requires a period of time to harvest and culture the T cells before the therapy can be administered to the patient. One of the major reasons for this time delay is the fact that tumour specific T-cells are generally present only at very low frequencies within the patients’ blood or tumour. More recent experimental work has focused upon the use of gene-therapy in order to more rapidly generate tumour specific T-cells. The gene therapy procedure involves the introduction of DNA into the T-cells at an early stage of culture that results in producing a protein on their surface and facilitates the specific targeting of tumour. In this case of ex-vivo gene therapy, the gene transfer vector is administered to the T-cells and is washed away before the cells are returned to the patient. In theory, this ensures that tumour specific T-cells can be generated more rapidly thereby potentially reducing the length of time required to generate the T-cells for therapy.

Clinical Developments in Manchester

The University Department of Medical Oncology based at Christie Hospital and the Paterson Institute for Cancer Research has been working upon the development of gene-modified T cells for cancer therapy. Two phase I clinical trials of T cells targeted against colorectal cancer and B-cell lymphoma have recently opened. Underpinning these trials has been the development of the infrastructure to deliver cell therapies and, consequently, we are now collaborating with Dr Rosenberg’s group to develop TIL therapies. The development of this therapy has been also driven by the collaborative effort between Medical Oncology and the Department of Surgery based at Christie’s and we are currently performing developing our in-house protocols in order to submit proposals for phase I trial to the Regulatory agencies. We are also currently initiating studies aimed at developing gene-modified T cells for melanoma therapy again in collaboration with Dr Rosenberg and colleagues. 

Why research?

All treatments have to be fully researched before they can be adopted as standard treatment for everyone. This is so that:

• We can be sure they work
• We can be sure they work better than the treatments that are available at the moment
• They are known to be safe
• The research process
• First, treatments are developed and tested in laboratories. For ethical and safety reasons, experimental treatments must be tested in the laboratory before they can be tried in patients. If a treatment described here is said to be at the laboratory stage of research, it is not ready for patients and is not available as a treatment either in the NHS or in private health care.

Tests in patients are called clinical trials. There are 4 phases of clinical trials. This is fully explained in the understanding clinical trials section of CancerHelp UK.

Until studies are completed and new effective treatments are found, these treatments cannot be used as standard therapy for melanoma.

Prevention and detection

Most melanomas are preventable. If we can find a way to successfully educate people not to go out in the sun without protecting their skin we could prevent the majority of skin cancers. Research into this area includes:-

• National skin cancer prevention campaigns
• Melatonan skin pellets and sun protection
• Genetics
• Preventing melanoma coming back after treatment
• Skin cancer prevention campaigns

Late in 2002, the UK Health Departments commissioned Cancer Research UK to run a national skin cancer prevention awareness campaign. The campaign called SunSmart, was launched in March 2003. This pilot year was to pave the way for a continuous campaign for a further 3 to 5 years.

Cancer Research UK commissioned the Office for National Statistics (ONS) to carry out a sun protection survey in March 2003. This survey was designed to measure:-

• Knowledge about ways to prevent skin cancer
• Attitudes to tanning and the dangers of the sun
• How people protect themselves in the sun
• You can download the results from the ONS 2003 survey from the Cancer Research UK website.

Genetics

Scientists now know that the ultraviolet light from the sun damages your DNA. These changes in your DNA cause normal skin cells to become cancerous. Scientists are using this information to develop new treatments for skin cancers.

A few people are more at risk of developing melanoma than other people, because they have inherited a high-risk faulty gene from a relative. Scientists recently discovered one of these genes, called the p16 gene or CDKN2A. They are running a long-term study to find out more about how genes and your surroundings can affect your risk of developing melanoma. You may be able to take part in this study if you have had more than one melanoma, or if you have had a melanoma and have at least 2 relatives who have also had melanoma. You will have a blood test and be asked about your family history and your lifestyle. If you take part in this study, it will not make any difference to your treatment. There is more information about this study in our clinical trials database. It is not recommended that everyone has a test for gene faults. This is because the gene is rare and advice offered to families with melanoma on prevention and regular screening for early signs is the same whether you are carrying the gene or not.

Preventing melanoma coming back after treatment

A study is looking into how people live, what they eat, and how much time they spend in the sun after they have been treated, to see if any of these factors might increase the risk of the melanoma coming back. This study will also look at the genes of people with melanoma, to find out if any of these affect the risk of recurrence.

Biological therapy

Biological therapy is treatment with substances that are made naturally within the body. Immunotherapy is a type of biological therapy. Immunotherapy works by encouraging the body's natural defence system - the immune system - to attack cancer cells. There is some general information on immunotherapy in the biological therapy section of CancerHelp UK. The types of biological therapies being researched for melanoma include:-

• Interferon
• Tumour necrosis factor
• Vaccines
• Gene therapy
• Interferon
• Early stage melanoma is usually treated with surgery. For some people, there is a risk that the melanoma will come back at some time after their surgery. Doctors are trying to find out if immunotherapy treatments may help to prevent this. One type of immunotherapy used for melanoma is interferon. Interferon is made naturally as part of the body's immune response. But it can be made in the laboratory and used in much larger quantities as treatment for cancer and other diseases.

There has been a trial of interferon for people with stage 3 melanoma. The trial aims to find out if giving interferon lowers the risk of the melanoma coming back after surgery. This trial is now closed.

Interferon has also been tried for melanomas that have spread to other parts of the body. It hasn't been shown to be of much benefit so far.

Tumour necrosis factor (TNF)

This is another immunotherapy that has been tried, along with chemotherapy, in regional limb perfusion. Regional limb perfusion is a way of giving drug treatment to just one arm or leg that is affected by melanoma. It is usually used for melanoma that has come back in the same limb after it was first treated. This type of treatment is very experimental. More trials are needed before we know if it will help people with melanoma.

Vaccines

Cancer vaccines are a fairly new area of research. Vaccines have shown some promise as a potential new treatment for melanoma. Vaccines may help your immune system to kill the cancer cells. The phase 3 trials that have been done so far have had disappointing results. But research into these vaccines is continuing. A vaccine that is currently in trial is the PolyMEL DNA vaccine. This is a small trial open to people with melanoma that has spread. Doctors hope that the vaccine will teach the immune system to recognise proteins found on the cancer cells, so it will attack them. Because it is a DNA vaccine, you may also hear this referred to as gene therapy.

Gene therapy

This is one of the newer approaches to cancer treatment and is in the very early stages of clinical trials in the USA and UK. It really is early days. We are a long way from having gene therapy treatment for melanoma. We don't yet know if it will work at all.

By studying how changes in these genes cause normal cells in the skin to become cancerous, scientists aim to eventually develop gene therapy so that damaged genes in the cancer cells can be replaced with normal ones.

One example of gene therapy is with a drug called Augmerosen. This drug can stop cells from making a protein found in many melanoma cells. This protein stops the melanoma cells dying off, as normal cells eventually would. In very early studies, people with advanced melanomas were given Augmerosen with a chemotherapy drug called dacarbazine (DTIC). In some people the melanomas shrank. This is a very early phase trial and we don't know how effective this drug is in treating melanoma.

There is general information about gene therapy in the biological therapy section.

Monoclonal antibodies

Antibodies are proteins made by the cells of the immune system when they come across something they don’t recognise, for example an infection. The antibodies attach themselves to the invading bacteria or viruses and kill them. Our bodies make many different antibodies as part of our immune system's reaction to infection or damaged cells. Each antibody recognises one particular protein on the surface of a foreign or invading cell.

A monoclonal antibody (MAB) is a copy of a single antibody made in the lab that can be made in bulk. 'Monoclonal' just means 'all one type'. In cancer, each monoclonal antibody treatment is specific to one particular protein found on the surface of the cancer cell.

An MAB called ipilimumab has been tested for people with stage 3 or 4 melanoma. People on the trial had dacarbazine chemotherapy, and either ipilimumab or a dummy (placebo) treatment. Doctors want to find out if ipilimumab and dacarbazine work better together than dacarbazine on its own. They also want to find out more about the side effects of ipilimumab.

A monoclonal antibody called CNTO 95 has been tried to see how well it works against advanced melanoma. Doctors hope that CNTO 95 will make it difficult for the cancer cells to develop a blood supply. They want to find out what the best dose is, and whether adding it to treatment with the chemotherapy drug dacarbazine (DTIC) works better than dacarbazine on its own.

Another monoclonal antibody is bevacizumab. This is licensed as a treatment for advanced bowel cancer, and has also been used for other cancers. Doctors want to find out if giving it to people with high risk melanoma helps to stop the cancer coming back, after it has been removed surgically. There is a trial to look into this.

Chemotherapy and other drugs

This isn't usually the first choice of treatment but doctors may suggest chemotherapy for melanoma

If your cancer has come back

If your cancer is too advanced for surgery when it is diagnosed

Doctors have also used chemotherapy after surgery to try to lower the risk of the cancer coming back (adjuvant treatment). So far, there is no real evidence from research that adjuvant chemotherapy is helpful in stopping melanoma from coming back.

Dacarbazine (DTIC) has been tested more than any other chemotherapy drug for melanoma that has spread. It has had some success in controlling the melanoma for a time. Dacarbazine (DTIC) is usually the first choice of doctors using chemotherapy to treat melanoma.

A newer chemotherapy drug called temozolomide (Temodal) has had some success in treating brain tumours. A trial called EORTC 18032 has been comparing temozolomide with dacarbazine for advanced melanoma. The researchers want to find out which works best in this situation.

This information has been taken from the Cancer Research UK website. We will bring you information from Dr Lorigan and his team in the coming months.