Melanoma is a deadly tumor which in recent years has been successfully treated with immune checkpoint inhibitors as PD-1/PD-L1 and CTLA-4 inhibitors and targeted therapy as BRAF and MEK inhibitors.
Antitumor activity with or without anti-CTLA4 monoclonal antibody (mAb) therapy has been observed in patients with melanoma, and major tumor regressions have been observed in patients with pancreatic cancer, mesothelioma, and other tumors in combination with chemotherapy.
In vivo experiments using a B16F10 mouse melanoma model demonstrate that the active delivery of anti-CTLA-4 (a checkpoint inhibitor drug) results in greatly enhanced immune response and significantly longer survival.
Immune checkpoint inhibitors targeting the cytotoxic T lymphocyte-associated antigen-4 and programmed cell death-1 receptors have transformed the treatment of melanoma and other cancers.
Antibody-mediated targeting of regulatory T cell receptors such as CTLA-4 enhances antitumor immune responses against several cancer entities including malignant melanoma.
Two types of immune checkpoint inhibitors, both antibodies that target CTLA-4 and PD-1, have been approved for its use in NSCLC and melanoma as first-line or second-line therapy.
Immune checkpoint inhibitor-based cancer therapies targeting the co-inhibitory receptors CTLA-4 or PD-1 have received enormous scientific and clinical attention during the last few years, because of promising clinical results observed in the treatment of different cancer entities including melanoma and cutaneous squamous cell carcinoma.
After a 20-year era of adjuvant interferon, the anti-CTLA-4 and anti-PD-1 immune-checkpoint inhibitors, and MAPK-directed targeted therapy brought a revolution into the adjuvant treatment of melanoma.
In addition, the combination of antibodies to CTLA-4 (ipilimumab) and to PD-1 (nivolumab) has been found to confer a survival benefit in patients with melanoma or renal cell carcinoma.
The CYTOX score is predictive of severe immune-related toxicity in patients with melanoma treated with combination anti-CTLA-4 and anti-PD-1 immunotherapy.
In contrast, the combinations of CTLA4/PD-1 checkpoint inhibitors in renal cancer and melanoma show no more activity than that predicted by the independent contributions of the monotherapies.
Anti-Cytotoxic T Lymphocyte Antigen 4 (Anti-CTLA4) rechallenge and a sequential administration of anti-CTLA4 and anti-Programmed cell Death protein 1 (anti-PD1) or Anti-Programmed Death Ligand 1 (anti-PDL1) agents have been explored in melanoma patients in several clinical trials while the anti-PD1/anti-PDL1 rechallenge has been little investigated.
Combined PD-1 and CTLA-4-targeted immunotherapy with nivolumab and ipilimumab is effective against melanoma, renal cell carcinoma and non-small-cell lung cancer<sup>1-3</sup>.
A retrospective study was conducted at two centers and included patients with melanoma who underwent surgery after treatment with monotherapy or combination therapy with anti-programmed cell death protein (PD) 1 and/or anti-cytotoxic T-lymphocyte associated protein (CTLA)-4 checkpoint blockade.
Immune checkpoint inhibitors (ICIs), including inhibitors of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) have demonstrated prominent clinical benefits in a variety of cancers and have been rapidly applied to treat a variety of carcinomas such as melanoma, non-small-cell lung cancer, and head and neck cancer.
Melanoma treatment has progressed in the past decade with the development and approval of immune checkpoint inhibitors targeting programmed death 1 (PD-1) or its ligand (PD-L1) and cytotoxic T lymphocyte-associated antigen 4, as well as small molecule inhibitors of BRAF and/or MEK for the subgroup of patients with BRAF<sup>V600</sup> mutations<sup>1-9</sup>.
Cytotoxic T-lymphocyte-associated protein 4 expressed by melanoma cells does not affect melanoma-specific cytotoxic T lymphocytes in the effector phase.
The introduction of the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) immune checkpoint inhibitors and their subsequent listing on the Pharmaceutical Benefits Scheme for use in metastatic melanomas, renal cell carcinomas and non-small-cell lung cancers has resulted in routine use of these agents in oncology practices, including in regional areas.
Antibody-mediated blockade of immune checkpoint molecules PD-1/PD-L1 and CTLA-4 has had a dramatic impact upon the treatment of previously intractable cancers such as malignant melanoma, while adoptive cell therapies using chimeric antigen receptor-bearing T cells have proven highly efficacious in B cell leukemia.