Although immunotherapy with anti-CTLA-4 and anti-PD-1 agents has dramatically changed the treatment approach to cutaneous melanoma, its success in uveal melanoma has been much more limited.
Eligible patients were at least 18 years old, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, at least one measurable lesion per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), unresectable stage III or IV melanoma (excluding ocular melanoma), and up to one previous systemic therapy (excluding anti-CTLA-4, PD-1, or PD-L1 agents).
Immune checkpoint inhibitors targeting cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and programmable cell death protein 1 (PD-1)/PD-L1 have shown antitumor activity in cancers such as melanoma, non-small cell lung cancer, renal cell carcinoma, and urothelial cancer.
Immune-checkpoint inhibitor (ICPI) drugs, which include antibodies against CTLA-4, PD-1 and PD-L1, have been shown to induce durable complete responses in a proportion of patients with particular efficacy demonstrated in both the first line and refractory setting in advanced NSCLC and melanoma.
Indeed, phase III clinical trials have revealed that therapies such as ipilimumab and pembrolizumab which target the CTLA4 and PD-1 immune checkpoints, respectively, have raised the three-year survival of patients with melanoma to ∼70%, and overall survival (>5years) to ∼30%.
Immunotherapy using checkpoint-blocking antibodies against targets such as CTLA-4 and PD-1 can cure melanoma and non-small cell lung cancer in a subset of patients.
Fighting cancer with immunotherapy has revolutionized treatment for some patients and therapies targeting the immune checkpoint molecules such as CTLA-4 and PD-1 have achieved durable responses in melanoma, renal cancer, Hodgkin's diseases and lung cancer.
Immune checkpoint inhibitors, which target PD-1 and CTLA-4, have been shown to be effective in other cancers such as melanoma; however, they have not demonstrated outcome benefits in PDA so far.
Indeed, antibodies binding to CTLA-4, PD-1, or PD-L1 have shown remarkable efficacy, especially in combination therapies, for a number of cancers and have been licensed for the treatment of melanoma, nonsmall cell lung cancer, and renal and bladder cancers.
Peritumoral injections of PlGF-2<sub>123-144</sub>-anti-CTLA4 (cytotoxic T lymphocyte antigen 4) and PlGF-2<sub>123-144</sub>-anti-PD-L1 (programmed death ligand 1) Abs delayed tumor growth and prolonged survival compared to the unmodified Abs in genetically engineered murine tumor models of melanoma and breast cancer.
Ipilimumab is a human monoclonal antibody that functions as a cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitor that is used to treat malignant melanoma.
First results in unresectable and metastatic melanoma patients treated with an anti CTLA-4 monoclonal antibody showed an unexpected 3-year overall survival of at least 25%.Lung cancer cells have multiple immunosuppressive mechanisms that allow to escape of the immune system and survive, however blocking CTLA-4 pathway with antibodies as monotherapy treatment have not achieved same results than in melanoma patients.
Initial evidence, for example with combined inhibition of PD-1 and CTLA-4 in melanoma and non-small cell lung cancer (NSCLC), has highlighted the potential to further enhance the clinical benefits of monotherapies by combining agents with synergistic mechanisms of action.
Here, we show that Aire deficiency in mice expands the pool of CD4+ T cells capable of melanoma cell eradication and has additive effects with anti-CTLA-4 antibody in slowing melanoma tumor growth and increasing survival.
Ipilimumab (a monoclonal antibody against CTLA-4) and nivolumab (a humanized antibody against PD-1) target these immune checkpoint pathways and are used for treatment of melanoma and an increasing number of other cancers.
Treatment with a combination of a proprietary formulation of coxsackievirus and either an anti-CTLA-4 or anti-PD-1 checkpoint inhibitor yielded a higher response rate in phase I testing for melanoma than any of these drugs given on their own.
Altogether, these results indicate the identification of a novel mechanism underlying melanoma progression in the present study and that CTLA-4-targeted therapy may benefit candidate CTLA-4-targeted therapy by improving the long-term outcome for patients with advanced stages of melanoma.
Immune checkpoint inhibitors (anti-CTLA-4, anti-PD-1, or the combination) enhance anti-tumor immune responses, yielding durable clinical benefit in several cancer types, including melanoma.
This review examines the mechanisms of action and the limitations of anti-PD-1/PD-L1 and anti-CTLA-4 antibodies which are the two types of checkpoint inhibitors currently available to patients and further explores the future avenues of their use in melanoma and other cancers.