Immunotherapy

In most patients, melanoma in the skin creates an immune response against itself. This is seen in the partial regression of primary melanoma on the skin. In some instances the primary melanoma disappears completely from the skin, but not before melanoma cells spread from the skin to other sites in the body, such as regional lymph nodes. This is referred to as occult melanoma.

Once melanoma has spread from the skin, natural responses by the immune system are less effective in controlling tumour growth. This may be because the immune response is less effective in particular parts of the body to which melanoma has spread or because the tumour cells undergo changes which make them less susceptible to the immune system. Over time, interaction between melanoma cells and the immune system also leads to change in immune responses that make them less effective in killing melanoma cells. These changes lead to the tumour becoming “immunologically silent” in patients.

Various strategies are being tested to use immunotherapy against melanoma. Immunisation with melanoma vaccines aims to increase immune responses against the patient’s melanoma and to change the nature of the immune response to be more effective against melanoma. At present, the following programs are in progress:

• Immunisation with Dendritic Cell Vaccines
• Immunisation with Extracts of the Patient’s Melanoma
• Immunisation with “Allogeneic” Vaccines or Synthetic Melanoma Antigens
• Interferon

Immunisation with Dendritic Cell Vaccines

Dendritic cells (DCs) are responsible for presenting melanoma antigens to T cells in the immune system and for directing the nature of the response. It is believed that DCs in patients may not present antigen satisfactorily to the T cells but if isolated from the patient and activated in the laboratory with various agents they will be able to once more activate the immune response.

Patients being treated with DC vaccines must have measurable tumors and be prepared to make regular visits to the SMU over a 16 week period. DCs are isolated from the patient’s blood and grown in the laboratory for 7 days. Melanoma antigen in the form of extracts from the patient’s tumor or from synthetic preparations are added to the DCs and injected into regional lymph nodes – usually those in the groin. Injections are at weekly intervals for the first 4 injections, one is given 2 weeks later, then 2 at 4 weekly intervals. Side effects have been minimal.

Immunisation with Extracts of the Patient’s Melanoma

It is considered that immunisation with vaccines prepared from a patient’s tumor, away from the site of the patient’s melanoma and mixed with helper antigens, may activate or increase responses against the patient’s tumor.

One such vaccine was prepared from so-called heat shock proteins in the melanoma cell. This vaccine was prepared by a firm called “Antigenics” in the USA. Outcomes are being evaluated from the randomised trial comparing vaccine treatment with standard chemotherapy.

Patients who have surgically removable tumor but who are not eligible for any trial may be offered treatment with vaccines prepared from their tumor on a compassionate basis. These treatments are not being evaluated in a trial setting and evidence of benefit is largely anecdotal.

Immunisation with “Allogeneic” Vaccines or Synthetic Melanoma Antigens

Many patients do not have melanoma available for preparation of vaccines from their tumor.

In view of this, patients may be offered treatment with a standard vaccine prepared from a melanoma cell line that has been infected with vaccinia virus. The latter virus has been used to immunise people against smallpox, but in this setting is used to lyse the melanoma cells and to increase immune responses against the melanoma antigens. The vaccine (VMCL) has been evaluated in a randomised trial in Australia. It was associated with an approximate 10% increase in survival at 5 years and 20% at 10 years but the significance tests did not exclude that the results may have been due to chance. No significant side effects were associated with the treatment. Results were published in the Journal of Clinical Oncology, Volume 20, Pages 4181-4190, 2002.

In the Newcastle Melanoma Unit, patients may also be offered immunotherapy with a vaccine prepared from small peptides that contain the immunogenic part of several melanoma antigens. The injections are given each 2 weeks over 12 weeks. Patients must have measurable melanoma to be eligible for the study.

Interferon

The interferons are a family of proteins produced by the body’s immune system. They serve a variety of purposes, including helping to defend against viruses, like influenza. There is good laboratory evidence, and some clinical evidence, that they also work to kill melanoma cells, both directly and also by stimulating the immune system to attack the cancer cells. The main interferon that works against melanoma is called interferon-alpha.

For over 10 years a vigorous debate has taken place between melanoma specialists as to whether or not interferon protects people from recurrence of melanoma, once they have had a melanoma removed.

Throughout the 1980’s and '90’s a series of clinical trials was performed in the USA and Europe to investigate the use of interferon-alpha in reducing the risk of recurrence after high-risk melanoma had been removed. Unfortunately, the results of those trials were very confusing due to different groups of patients tested, different dosage schedules chosen, and other factors.

There is now fairly good evidence that low dose and intermediate dose interferon have little effect, but a serious question mark remains over the use of high-dose interferon, or “HDI”. Three trials suggest that HDI significantly prolongs the time between the initial melanoma and any relapse that may occur. However, HDI involves giving the drug via a drip into the vein daily for a month as an outpatient. The side-effects of this treatment are considerable, and may include fevers, fatigue, muscle pains and mood disturbance. Many of these side-effects can be controlled and modified, but patients receiving the treatment require careful monitoring and special nursing care.

For this reason it is enormously important that further research is undertaken to find out whether this treatment protects against melanoma recurrence. If so, most patients would gladly tolerate a month of relative discomfort for the protection gained.