Key learning points:
– The treatment of the lethal skin cancer malignant melanoma has been transformed with the regulatory approval of new antibodies, which can activate patient immune responses
– Patients who benefit from these checkpoint antibodies appear to have durable responses
– Checkpoint blockade antibodies suffer from notable toxicities and only a proportion of patients respond to these treatments; highlighting the need to develop better predictive tools
Malignant melanoma is a type of skin cancer caused by a cancerous change in skin pigment cells known as melanocytes. Although melanoma accounts for only 5% of all skin cancers, it is responsible for the majority of skin cancer related deaths. (1) Melanoma is more prevalent in white populations and is thought to be predominantly attributable to exposure to damaging UV radiation from sunlight. Despite multiple campaigns and increasing awareness, the incidence of melanoma has risen four-fold in the last 30 years, affecting both young and old individuals, and is predicted to keep rising. (2) This translates to around 13,000 new cases per year in the UK and around 75,000 in the USA. It is currently estimated that 112,000 people in the UK are living with malignant melanoma. In the UK, around 2,200 deaths per year are attributed to melanoma, and in the USA the figure is around 9,500 per year. (3,4)
Surgical excision in the early stages of the disease is associated with a good prognosis, however overall around 20% of patients diagnosed with melanoma will go on to develop distant metastases for which the outlook is poor with a median survival of around seven months. The risk of development of metastatic disease can in part be predicted by disease staging using information regarding the primary tumour (thickness, presence of ulceration and mitotic rate) in addition to assessment of local skin draining lymph nodes utilising a technique known as sentinel node biopsy. (5) However, there is a need for less invasive and more accurate prognostic tools for this type of cancer. Although recent advances in treatment for advanced stages of disease outlined in this article have provided much hope for patients with this condition, only a limited number of patients will develop long term, durable responses to treatment. Further work is required to more accurately stratify patients in order to optimise treatment response.
Until recently, few treatment options were available for melanoma patients with advanced disease. The first treatment that offered any promise was the chemotherapeutic agent dacarbazine (DTIC), approved in 1975, and it remained the gold standard of therapy for several decades, in spite of minimal impact on overall survival outcomes. The subsequent regulatory approval of the multifunctional immune activatory cytokines interleukin 2 (IL-2), and interferon alpha (IFNα) held some promise, but because of significant toxicity and lack of sufficient impact on survival outcomes, neither drug is administered routinely in patients to the UK.
More recently, treatments that mobilise the patient’s own immune system against cancer (immunotherapy) are proving to be an exciting new approach in oncology. Such new therapeutic approaches have stemmed from a large volume of evidence gathered over many years that suggest that cancer, and importantly also melanoma, interacts with our immune response, and that cancer cells can suppress key components of our immune system to their advantage. The rationale for immunotherapy is therefore based on the hypothesis that if we can target certain elements of immunity, we can wake up the patients’ immune response to become destructive to cancer cells.
Monoclonal antibodies are a form of biological therapy (or immunotherapy) that can be readily generated in the laboratory and are designed to specifically recognise molecules (antigens) on the surface of target cells such as melanoma cells. The binding of the antibody onto the tumour cell can result in a deleterious alteration in the function of the cell or even destroy it. In addition, binding of an antibody to a tumour cell can also further enhance the anti-tumour immune response by alerting the rest of the immune system to the presence of a tumour by binding to immune cells in addition to the tumour.
Following decades of research to design clinically-useful agents, these attributes of antibodies have now been harnessed for the generation of a recent group of antibody therapies, known as checkpoint blockade antibodies. These antibodies are designed to block the effects of molecules expressed on immune cells known as T Lymphocytes that have a negative impact on the anti-tumour immune response. After binding to these checkpoint molecules, antibodies can specifically release the break that prevents T Cells from eliminating cancer cells.
The first of these agents, Ipilimumab (YERVOY), recognises the checkpoint molecule cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) on the surface of T Cells. One of the functions of ipilimumab is thought to be the direct activation of potentially cytotoxic T Cells by blocking CTLA-4 that is responsible for down-regulating T Cells activation. This blockade can release the power of t-cells to then destroy melanoma cells. More recent evidence suggests that the antibody also wakes up important immune effector cells, such as macrophages to directly target and destroy a specific sub-population of tumour-resident T Cells termed regulatory T Cells (Tregs) or whose role is also to suppress immune responses. It therefore seems that ipilimumab functions through different mechanisms, namely reducing immune suppressive signals associated with tumours and also by switching on immune cells in patients.
The regulatory approval of ipilimumab by the USA Food and Drug Administration (FDA) for the treatment of advanced metastatic melanoma (developed by Bristol Myers Squibb) in 2011 marked a significant milestone in oncology, constituting a major advance as the first immunotherapy and also the first antibody to show clinical efficacy for this lethal cancer.
In 2010 a study showed a median survival of 10 months in patients with advanced melanoma who were treated with ipilimumab, compared with six months for those patients treated with an experimental vaccine. (6)
Although ipilimumab is an effective therapy in some patients, it suffers a notable toxicity profile and has been associated with severe immunological adverse effects due to generalised systemic T Cells activation, as ipilimumab activates all T Cells that express CTLA-4 irrespective of their capacity to recognise cancer cells. Many of the common serious adverse effects are associated with inflammation of the gastro-intestinal tract and include stomach pain, bloating, constipation or diarrhoea, however skin rashes, fever and breathing problems are also seen. Unfortunately the response rate is modest, with responses in around 20% of ipilimumab recipients only. (7) Encouragingly, for these patients who respond to the treatment, ipilimumab often appears to confer long-term responses, some greater than two years. Research is now being conducted to examine the reasons why patients don’t respond to the therapy and to search for biomarkers that predict which patients are likely to benefit from receiving treatment. Importantly, the search is still ongoing for more selective and effective antibodies and other targeted therapies.
A recent important development is the FDA accelerated approval of pembrolizumab (KEYTRUDA) for the treatment of advanced melanoma in September 2014, and of nivolumab (OPDIVO) in December 2014. (8,9) Pembrolizumab and nivolumab also belong to the checkpoint antibody family and targets the programmed death receptor 1 (PD-1), another immune checkpoint molecule on the surface of T Cells. PD-1 prevents full activation of T Cells through its interaction with its ligands, PD-L1 and PD-L2 on the surface of cancer cells and also of healthy cells. (10) While CTLA-4 blocks early T Cells activation, PD-1 may act at a later stage, reducing T Cells responses in patient lymph node or tumour lesions. Pembrolizumab and nivolumab are thought to interfere with these inhibitory signals by blocking the interactions of PD-1 with its ligands. This may allow the cytotoxic T cells to target tumour cells more effectively. Early data indicated an overall response rate of 24% in early clinical studies. Similarly to ipilimumab, pembrolizumab and nivolumab are also associated with immune-mediated side-effects, perhaps because interfering with PD-1 interactions with its ligands can affect both cancer and healthy tissues.
In addition to advances in treatment of melanoma by agents that directly influence the immune response, promise has also been shown with the use of small molecule inhibitors that target specific genetic mutations that are commonly seen in tumours. The small molecule kinase inhibitor vemurafenib was approved by the FDA for use in advanced melanoma in 2011 around the same time as ipilimumab. Vemurafenib is a kinase inhibitor specific for the V600E mutant form of BRAF kinase which is present in approximately 60% of melanomas. Although the use of this drug results in a rapid response in approximately 50% of patients, unfortunately the majority of patients relapse after a few months as the tumour becomes able to escape inhibition through the pathway that is targeted by this agent. (11) Unlike ipilimumab, durable responses are rarely seen. The use of verumafenib is seen in association with side effects most commonly skin rash, photosensitivity and the development of squamoproliferative skin lesions. More recently dabrafenib, which also targets mutant BRAF, has been used to treat patients and is thought to be associated with less phototoxicity. (12) Trametinib, another small molecule inhibitor that targets mitogen-activated protein kinase (MEK), a molecule that participates in the same signalling pathway inside cancer cells to support tumour survival, was also approved in 2013 by the FDA and may help to prevent the development of resistance to treatment with small molecule inhibitors. (13)
Several agents are now used in routine clinical practice in the UK, including verumafenib and ipilimumab, having received approval from the National Institute of Health and Care Excellence. However, optimum treatment regimes are currently under evaluation. Based on these exciting developments, the field of immunotherapy and antibody therapeutics is likely to expand in oncology, with an exponential increase in the number of clinical trials performed for these and other novel agents alone and in combination. (14) New agents, including novel engineered antibodies with enhanced binding to immune cells and the ability to activate these cells in tissues against cancer cells with high specificity. In addition to biological drugs better able to focus different components of patient immune responses against cancer cells are expected to reach clinical application in the near future. Improved designs of similar therapies with better attributes such as higher specificity for tumours, and agents less likely to destroy healthy tissues is also expected to yield more favourable safety profiles and improve patient outcomes.
The authors received support from the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.
Skin cancer statistics
NICE technology appraisal TA268 ipilimumab for treating locally advanced or metastatic malignant melanoma
U.S. approves Merck immune-stimulating drug for melanoma
Merck Receives Accelerated Approval of KEYTRUDA® (pembrolizumab), the First FDA-Approved Anti-PD-1 Therapy
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