Tractable tumors

Melanoma

The first drug approved for cancer immunotherapy is currently used for metastatic melanoma, a highly severe condition for which traditional treatments have proven to be poorly effective.

Melanoma is the most severe form of skin cancer and originates in melanocytes, the cells that synthesize the pigment melanin that color the skin.

The major risk factor for the development of melanoma is exposure to ultraviolet rays (UVA and UVB), i.e. to sunlight. Tanning beds and sun lamps also seem to be associated with an increased risk of developing melanoma.  In rare cases the presence of genes associated with inherited conditions to melanoma and treatment with immunosuppressive drugs used, for example, in organ transplant recipients.

Immunotherapy provides new weapons against metastatic melanoma: immune checkpoint inhibitors are drugs that activate a patient’s immune system to fight melanoma cells.

These intravenously-administered monoclonal antibodies inhibit the mechanisms adopted by melanoma to block the immune system, boosting the body’s immune defense against the tumor.

Future perspectives: the first results have been obtained in metastatic disease and more and more scientific evidence demonstrates the efficacy of these drugs also in other contexts of disease, as in the prevention of relapses in radically operated patients at high risk (adjuvant immunotherapy).

Melanoma is the first but not the only tumor in which the idea underlying immunoncology can be documented, i.e. to boost the immune system’s action against tumors.

Findings from studies in other tumors are encouraging, and therefore it is likely that an increasing number of patients will benefit from these highly innovative therapies in the next future.

Melanoma: what’s changed with Immunotherapy?

Recent advances in treatment strategies for melanoma have significantly improved survival, even in patients with advanced disease.

Dr. Anna Maria Di Giacomo, Medical Oncology and Immunotherapy, University Hospital of Siena, Italy

While surgery is the cornerstone of curative treatments in patients with operable disease, medical therapy is the elective treatment in advanced disease.

In this setting, melanoma is a research model that allowed scientists to understand the molecular basis of this type of cancer, as well as the mechanisms underlying its interaction with the host, and particularly with the immune system; this made it possible to make unprecedented progress in the medical treatment of advanced disease, and to obtain important benefits in the adjuvant setting in patients with a high risk of post-surgical recurrence.

The hypothesis that the immune system could protect the body from the development of tumors was first formulated early in the 20th century. However, experimental evidence was produced only in the middle of the 20th century, clearly defining the role of the immune system in controlling the development and growth of tumors.

During the last decades, a number of immunotherapeutic agents (e.g. cytokines, monoclonal antibodies, therapeutic vaccines, cytotoxic T cells, etc.) have been used, with varied fortunes, to test new immunotherapy strategies in melanoma patients.

Moreover, the body of knowledge acquired on this disease has also allowed to expand the application of immunotherapy to tumors of different histotypes in several clinical trials currently underway, and to develop a new class of therapeutic agents called immunomodulatory monoclonal antibodies.

The introduction of this class of drugs has been a turning point in the treatment of melanoma, and not only melanoma, due to the significant survival benefits observed in the last few years as compared to chemotherapy, and to its peculiar characteristics in terms of both treatment response kinetics and toxicity profile. The first of this new generation of monoclonal antibodies is ipilimumab, an antibody directed against CTLA-4 expressed on activated T cells, which enhances the anti-tumor activity of the immune system.

Treatment with ipilimumab has allowed to attain a long-term survival rate of 20%. However, we also realized that targeting PD-1 or its ligand PDL-1 could be a more effective strategy and provide a 100% increase in 5-year survival (about 35% of patients are still alive) when used in pre-treated patients; if we use this strategy as first line treatment, the proportion of patients still alive at 2 years exceeds 60%.

Moreover, if we use both antibodies in combination, we obtain earlier responses in more than 50% of patients, even in those who have a rapidly evolving disease or brain metastases, i.e. conditions with a more aggressive clinical course.

However, despite such important advances, about 50% of patients do not respond or respond for a limited period of time; several combination trials are currently underway with the objective to improve the efficacy of our standard therapies and to increase the rate of long-term survivors.