Immunotherapy for melanoma

What is immunotherapy?

Immunotherapy for cancers is based on the principle that the patient’s immune system is capable of generating immune responses against tumour cells. Melanomas are some of the most immunogenic tumours known and are therefore a good model system for immune-based vaccine therapies. Important developments in melanoma vaccines over the years include:

1. Understanding of antigen presentation and the role of T-cell activation in generating an anti-tumour response,
2. Identification of a number of melanoma-specific tumour antigens that are shared by tumours from different patients, and
3. Elucidation of T-cell recognition of specific peptide fragments that are expressed on the surface of tumour cells.

Immunotherapy for melanoma includes a number of different strategies with vaccines utilizing whole cell tumours, peptides, cytokine-mediated dendritic cells, and antibodies. Vaccines are currently under investigation to treat patients with advanced melanoma (metastatic melanoma), usually Stage III (melanoma spread to regional lymph nodes) or Stage IV (widespread disease).

See also Topical and intralesional immunotherapy for melanoma metastases.

The immune system

The immune system is known to function via two interdependent types of immune responses known as innate immunity and adaptive immunity.

Innate immunity

In innate immunity, an immediate immune response is triggered that signals immune cells to attack and contain tumour cell antigens until a long-term and more specific response can be generated.

Adaptive immunity

Adaptive immunity is a highly specific, long-lasting response to a particular antigen. Adaptive immunity will fight the existing antigen and enables the immune system to recognise and respond more rapidly to a subsequent encounter with the same antigen (immune memory).

The dendritic cells of the immune system are an important link between innate and adaptive immunity. Dendritic cells can capture antigens from surrounding tissue, and, if activated, present antigens to other cells of the adaptive immune system, including T cells and B cells.

In the adaptive immune response, B cells produce antigen-specific proteins, called antibodies, to mount an antigen-specific response. T cells can become either killer T-cells, called cytotoxic T cells (CTLs), which can directly kill foreign or aberrant cells, or mature into T-helper cells, which secrete proteins that stimulate other cells to participate in the immune response.

Whole cell tumour vaccines in melanoma immunotherapy

Whole tumour vaccines have the advantage of immunising the patient with diverse antigens that are present on the tumour surface without knowing the exact antigen(s) that may be responsible for tumour rejection, i.e. whole tumour cells are used as the source of antigen(s).

Autologous tumour vaccines: melanoma vaccines tailored to individual patients

Autologous tumour cells are derived from tumours surgically resected from patients who will be vaccinated with their own manipulated tumour cells. These tumour cells are irradiated or weakened in some fashion to prevent proliferation in the patient and reinjected into patients with or without medications that modify the immune reaction.

A limitation to autologous tumour vaccines is that a tumour specimen must be obtained from each patient. Autologous tumour vaccines require the surgical resection of a sample of the patient's melanoma, which can be irradiated or mechanically destroyed and given back to the patient to promote immune recognition.

Allogeneic cellular vaccines for melanoma

Vaccines have been generated using established stable cultured cell lines derived from tumours obtained from other patients. These are called allogeneic cellular vaccines.

Allogeneic tumour cell vaccines have melanoma-specific antigens that are shared by different patients. These shared antigens are immunogenic and can enhance the host’s immune system to generate an effective antitumour response. Allogeneic vaccines also have the advantage of being more readily applicable to a greater number of patients regardless of the availability of their own tumour cells. Two allogeneic vaccines have been evaluated in large-scale, randomised trials as an adjuvant therapy for melanoma.

Canvaxin® (Cancer Vax Corp, Carlsbad, CA, USA) is an allogeneic vaccine comprising of three viable irradiated melanoma cell lines. Whole cells are used. The cell lines were chosen for their high content of immunogenic melanoma and tumour-associated antigens, and contained at least 11 known tumour-associated antigens such as MAGE-1 (melanoma-associated antigen 1), MAGE-3, tyrosinase, gp100, gp75, and Mart-1 (melanoma-associated antigen recognised by T cells)/Melan-A. Multicentre randomised controlled trials compared Canvaxin® plus BCG to placebo plus BCG in both stage III and stage IV melanoma patients status post-surgical resection. The phase III trial for stage III melanoma patients reached the target number of enrolments and closed in September 2004. The phase III trial for stage IV patients was closed early, in April 2005. The development of Canvaxin has been discontinued in the USA, after the results of clinical trials determined the vaccine was not likely to increase survival in stage III disease.

Melacine® (Ribi ImmunoChem Research, Inc., Hamilton, MT, USA). Melacine consists of a mixture of two homogenised melanoma cell lines that are combined with the adjuvant DETOX ("detoxified Freund's adjuvant" comprising monophosphoryl lipid A and purified mycobacterial cell-wall skeleton). Based on studies in stage IV melanoma patients, Melacine was approved in Canada in May 2000 for treating advanced melanoma.

Defined antigen vaccines in melanoma immunotherapy

Allogeneic and autologous melanoma vaccines provide numerous potential antigens but the most important antigens remain unknown and monitoring the immune response has been challenging. The use of defined antigens has permitted the measurement of immune responses specific to those antigens.

Ganglioside vaccines in melanoma immunotherapy

Defined tumour antigens may be created synthetically. Several cell-surface molecules on melanoma cells may be targeted by antibodies, and antibodies to some of these molecules are induced in patients with melanoma.

A series of clinical studies have been performed with vaccines intended to induce humoral or B-cell responses to the melanoma antigen, GM2, a cell-surface ganglioside. In a pilot study, Livingston and colleagues showed a trend toward improved survival for patients with stage III disease who received GM2 ganglioside/BCG and low-dose chemotherapy, and they demonstrated that patients developed antibodies to the GM2 ganglioside. This led to a larger randomised phase III ECOG (Eastern Cooperative Oncology Group) study comparing GM2/KLH (xenogeneic protein keyhole limpet hemocyanin (KLH) in saponin-derived adjuvant QS-21 vaccine to high-dose interferon (IFN)α-2b. This study was recently closed due to higher survival rates in those treated with adjuvant IFN α-2b.

Peptide vaccines in melanoma immunotherapy

Peptide vaccines are intended to stimulate cell-mediated (T-cell) responses to tumour-specific antigens expressed on the surface of cells through a major histocompatibility complex (MHC) class I-restricted process.

The majority of peptide antigens are only weakly immunogenic, so they are typically delivered to the patient along with an immune adjuvant. These adjuvants, such as BCG or "incomplete Freund's adjuvant," are meant to induce inflammation and initiate the immune process.

Cytokines, such as interleukin (IL)-12 or granulocyte macrophage-colony stimulating factor (GM-CSF) have also been given simultaneously with these vaccines to further stimulate the immune response.

Melanoma cells can escape recognition and destruction by the immune system by hiding their antigens. Melanoma cells from different individuals express different antigens. Hence vaccines with multiple antigens may be more effective than those composed of a single antigen.

Clinical trials using peptide vaccines with epitopes MAGE-1, MAGE-3, MART-1, gp100, tyrosinase, and gp75 have been used for immunisation of stage III and IV patients.

Heat shock peptide vaccines in melanoma immunotherapy

A recent approach consists of using heat shock protein-peptide complexes (HSPPC) as vaccines. Heat shock proteins are stress proteins that "chaperone" antigenic proteins, alerting the immune system to eliminate the disease.

Peptide complexes extracted from melanoma cells can stimulate antigen-specific CD8+ T cells in the peripheral blood of melanoma patients. Preliminary data have indicated feasibility, minimal toxicity, and clinical responses in 18% of patients along with tumour-specific T-cell responses in 50% to 60% of subjects.

Currently, a phase III study is comparing a heat shock peptide vaccine (HSPPC-96) derived from autologous tumour to standard therapies (IL-2 and/or dacarbazine/temozolomide based therapy and/or complete tumour resection) in stage IV melanoma patients.

CpG DNA vaccines in melanoma immunotherapy

TLR9 is a toll-like receptor found in some immune cells (dendritic cells and B cells). It recognises a specific pattern of nucleotides found in bacteria and viruses known as CpG DNA. Synthetic CpG DNA agonists have been developed that bind to and activate TLR9.

TLR9 agonists initiate a cascade of cellular signals that result in a highly specific and targeted innate and adaptive immune response to infections and tumours, by generating cytotoxic T cells and disease-specific antibodies. TLR9 agonists activate dendritic cells to fight against the development of immune tolerance to pathogens and cancers.

CPG 7909 is a single-strand oligodeoxynucleotide TLR9 agonist that is being studied as an adjuvant to melanoma chemotherapy. A phase II study has been completed in patients with advanced melanoma and a phase III study will begin in patients with unresectable stage IIIb/c or stage IV melanoma.

Monoclonal CTLA4 antibody in melanoma immunotherapy

Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) decreases T-cell function and so reduces the effectiveness of cancer vaccines. Ipilimumab is a monoclonal antibody that blocks CTLA4 and has showed increased tumour immunity in previously vaccinated stage IV melanoma. To date, side effects of ipilimumab have included skin eruptions and itching in one-third of patients.

A randomised phase III double blind trial evaluated the effectiveness of ipilimumab alone or in combination with a vaccine MDX-1379 (a peptide vaccine made up of two peptides from the melanoma protein gp100). Because these peptides bind to HLA-A2 which is recognised by T-cells, only patients with stage III or IV previously treated melanoma (with unresectable disease) who are HLA-A*0201 positive were eligible. Recently published results of this trial have shown significant overall survival benefit with ipilimumab compared with a cancer vaccine comprising HLA-A*0201–restricted peptides derived from the melanosomal protein, glycoprotein 100 (gp100) in patients with metastatic melanoma, previously treated unsuccessfully with aldesleukin, dacarbazine, temozolomide, fotemustine, or carboplatin.

Based on phase III study results, The U.S. Food and Drug Administration (FDA) approved ipilimumab to treat patients with late-stage (metastatic) melanoma in March 2011. Ipilimumab is the first therapy approved by the FDA to clearly demonstrate that patients with metastatic melanoma live longer by taking this treatment. The therapy is being approved with a Risk Evaluation and Mitigation Strategy to inform health care professionals and patients about the risks of the treatment.

Cytokine and growth factor modulation in melanoma immunotherapy

Cytokines are soluble proteins that are important in the regulatory function of the cells of the immune system. Cytokines that have been used clinically to treat patients with cancer include IL-2, IFN-α, IFN-β, IFN-γ, GM-CSF, and TNF (tumour necrosis factor).

• Intravenous administration of recombinant IL-2 has been used in clinical trials for patients with metastatic melanoma with overall response rates of approximately 20%.
• Recombinant humanised (rh)GM-CSF in addition to autologous tumour vaccine was used to treat patients with metastatic melanoma with response rates of 20% and a 10% complete response rate.
• The FDA has approved IL-2 and INF-α for the treatment of melanoma. However, there are significant side effects including, 'flu-like symptoms, muscle aches, skin rash, fever, weakness, nausea and diarrhoea.

Administration of melanoma vaccines

Nursing advice for melanoma vaccines should include:

• Don't give injection into a limb that had the primary melanoma
• Rotate injection sites
• Warn patient of possible 'flu-like symptoms
• Observe patient for sterile abscess or infection at injection site
• Instruct patient to expect minor localised soreness, irritation, swelling, and discomfort at the injection site
• Assess and document the patient's allergy history
• Follow strict preparation and administration guidelines
• Use correct route: deep subcutaneous, intramuscular, or intradermal injection
• Select needle gauge according to study protocol
• Some protocols suggest that corticosteroids or immunosuppressive medications should not be given to patient while on vaccine
• Monitor patient for increased lymphadenopathy (swollen lymph glands)

Conclusions

There is a major collaborative effort in the United States and Europe involving the National Cancer Institute, pharmaceutical companies, hospitals, and institutes for research and development of cancer vaccines. More than 95 tumour vaccines are in development, many of which are for the treatment of melanoma patients.

Currently, the only immunotherapies approved by the US FDA for the treatment of melanoma are IL-2, INF-α2a and ipilimumab. At the present time, no melanoma vaccine has received approval from the FDA. A search of the National Institute of Health's clinical trials database reveals several phase III trials and many phase I and II trials investigating a variety of vaccines as monotherapy or in combination with other chemotherapy agents for the treatment of melanoma.

The use of melanoma tumour vaccines is currently (June 2011) not included in the National Comprehensive Cancer Network's 2010 practice guideline for the management of melanoma. The American Cancer Society (2010) noted "vaccines are experimental therapies that do not yet have proven benefit".

Note for readers

This article was written in June 2011. Immunotherapy for melanoma is a rapidly evolving field and the information may rapidly become outdated.

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