Unleashing the Immune System to Treat Metastatic Melanoma
Dating back in concept to the 1890s, modern cancer immunotherapy began in the 1980s with the approval of interferon-α2 (IFN- α2) to treat hairy cell leukemia. Subsequently, approval in the late 1990s of IFN-α2 and interleukin-2 (IL-2) for treatment of advanced or metastatic melanoma ushered in the era of immunotherapy as a treatment option for this cancer.1
The annual incidence of melanoma has increased significantly since 1975, reaching 76,690 in 2013; almost 9,500 die from this disease annually. For the 13% newly diagnosed at an advanced stage, prognosis is poor.2-4 Until the approval of ipilimumab, dacarbazine chemotherapy or IL-2 were the only approved therapies for these patients. Median survival times are roughly 9 and 11 months with dacarbazine and IL-2, respectively, and toxicity with IL-2 is substantial. While few achieve complete response (CR) with IL-2 (6%), 59% of those who do remain free of disease progression at 5 years.4
An effective immune response depends on an exquisite balance between stimulatory and inhibitory signals to T cells: too much stimulation can result in an autoimmune attack, while too much inhibition allows pathogenic cells (including tumors) to proliferate. Melanoma tumors present antigens to T cells and activate the immune system, but manage in most cases to evade destruction. Novel targeted immunotherapies unleash the immune system by blocking lymphocyte inhibitory receptors or ligands to enhance the antitumor activity of the immune system, taking advantage of the finding that inhibitory ligands and receptors involved in T cell effector functions often are overexpressed on tumor cells or in the surrounding microenvironment.2,5 Two such receptors have led to clinical development of immunotherapy with demonstrated antitumor activity in advanced or metastatic melanoma.
Cytotoxic T Lymphocyte–Associated Protein 4 (CTLA-4)
CTLA-4 is expressed only on activated T cells. It inhibits T cell function both directly through signaling, and indirectly by outcompeting the costimulatory molecule CD28 from binding with their shared ligands, CD80 and CD86. In so doing, CTLA-4 places a protective “brake” on immune response that is essential to self-tolerance and protection of normal cells as the immune system attacks pathogenic cells. In practice, CTLA-4 blockade enhances helper T cell–dependent immune response.5-7 The rationale for anti-CTLA-4 drugs is that blocking CTLA-4 frees CD80/CD86 to bind with costimulatory CD28, augmenting T-cell activation and allowing the immune system to attack the tumor. Two such drugs have reached phase 3 clinical trials; one, ipilimumab, was approved in 2011 for treatment of advanced melanoma.
Ipilimumab is a monoclonal antibody to CTLA-4; the standard dose is 3mg/kg administered intravenously every 3 weeks for four courses. It is the first treatment demonstrated to prolong survival in patients with metastatic melanoma (Table 1) and is a preferred regimen for advanced or metastatic melanoma in guidelines from the National Comprehensive Cancer Network. Patients who achieve CR tend to have durable responses (54–99 months). Long-term follow up of 177 patients from three ipilimumab clinical trials found 5-year survival rates of 13%, 23%, and 25%.2,4,5,8
A second CTLA-4 inhibitor, tremelimumab, showed efficacy against melanoma in phase 1/2 trials. In a phase 3 trial comparing it with chemotherapy (dacarbazine or temozolomide) in treatment-naïve advanced melanoma patients, tremelimumab failed to prolong overall survival (OS), which was the study's primary end point. The drug was not completely ineffective; median OS was 12.6 months and patients who achieved CR had durable responses. However, the study was ended early and further development of tremelimumab is in doubt.1,5,9