The incidence of melanoma has been increasing over the past twenty years. Melanoma diagnosed at an early stage and radically resected has the best chance for cure. However, the prognosis of the advanced-stage disease is still poor due to a lack of responsiveness to traditional chemotherapeutics. Advances have been made in the understanding of melanoma development and progression, resulting in the availability of promising novel therapeutic options in the clinic. Just overlapping with the development of targeted therapy such as kinase inhibitors, immune checkpoint therapies have gained attention. Durable and sometimes complete remission of metastatic melanoma is now achievable in some patients who receive checkpoint-blocking therapy.
The immune checkpoint inhibitors appear to open a new era to treat melanoma and other malignant neoplasias. Melanoma is the first cancer type to drive the use of immune-checkpoint inhibitors into clinical practice, which revolutionized the therapeutic paradigm not only in melanoma but also in an increasing number of tumors. Some agents targeting immune checkpoint have been the most extensively researched for the treatment of melanoma due to higher rates of tumor clearance and, crucially, long-term disease eradication in some patients. An impressive series of successful clinical trials initiates with the monoclonal antibodies (mAbs) against CTLA-4 and is followed with anti-PD-1 antibodies, as well as the combination of immune checkpoint therapy. These treatments based on immune checkpoints have achieved long-lasting responses and a 20-40% long survival rate.
Monoclonal antibody against CTLA-4 is FDA-approved for treating melanoma, leading to an improvement in the overall survival of patients with unresectable melanoma. Anti-CTLA-4 antibody leads groundbreaking research and paves the wave for further development of immune checkpoint inhibition (ICI) treatment modalities.
Anti-PD-1 checkpoint inhibitors have been approved for the treatment of advanced melanoma patients, with response rates of 40% and a demonstrated survival advantage in phase III trials.
As CTLA4 and PD-1 are distinct immune checkpoints, acting at different stages of the T cell activation, combinatory treatment with anti-CTLA-4 and anti-PD-1 antibodies provides additive or synergistic effects anti-melanoma immunity. Importantly, further research has emphasized improved response and survival rates when combining anti-CTLA-4 and anti-PD-1 therapy, leading to the approval of anti-PD-1 plus anti-CTLA-4 for the treatment of unresectable or metastatic melanoma in adults.
Table 1. The clinical development of immune checkpoint agents for melanoma.
| Target | Description | Phase |
| CTLA-4 | A fully human IgG1 mAb approved for use in melanoma patients at 3 mg/kg dose every 3 weeks for 4 doses | FDA approved |
| An IgG2 human mAb targeting CTLA-4 | Phase I/II | |
| PD-1 | A humanized anti-PD-1 mAb approved for the treatment of advanced melanoma patients | FDA approved |
| A fully human immunoglobulin G4 (IgG4) mAb anti-PD-1 agent | FDA approved | |
| PD-L1 | An anti-PD-L1 humanized IgG4 mAb is tested in pretreated patients with solid tumors, including melanoma | Phase I/II |
| A high-affinity anti-PD-L1 human IgG1 mAb tested in patients with advanced melanoma | Phase I | |
| Tested in patients with various solid tumors, including melanoma | Phase I | |
| LAG-3 | The human IgG4 monoclonal LAG-3 antibody in combination with anti-PD-1 mAb monotherapy for first-line advanced melanoma treatment | Phase II/III |
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