Immune Checkpoint Inhibitors in the Treatment of Melanoma: From Basic Science to Clinical Application

Abstract

Abstract:Immune checkpoint blockade has revolutionized the treatment of patients with advanced melanoma and many other cancers. Blockade of inhibitory receptors, CTLA-4 and PD-1, enhances T-cell-mediated antitumor immune responses, leading to improved survival and durable responses in patients. Based on their mechanism of action, immune checkpoint inhibitors can also induce immune-related adverse events that require careful monitoring and prompt treatment. Despite these successes, only a fraction of patients benefit from immune checkpoint blockade. Basic science approaches and clinical experience are defining predictive biomarkers to identify patients most likely to respond to therapy as well as mechanisms of resistance that limit responses in certain tumors or shorten the duration of response. New approaches and combination therapies are under development to broaden the clinical impact of immune checkpoint blockade by overcoming resistance to therapy and limiting adverse events.

Overexpression of CDCA8 promotes the malignant progression of cutaneous melanoma and leads to poor prognosis

“…In 2014, there were >76,000 new cases of melanoma in the United States and >9,000 patients succumbed to melanoma ( 4 ). Sadly, at present, the 5-year overall survival (OS) rate for patients with stage IV melanoma is <15% ( 5 , 6 ) Furthermore, patients suffering from metastatic melanoma have a poor prognosis ( 1 , 3 ). Thus, identifying novel biomarkers related to the prognosis and progression of melanoma may improve the treatment and outcomes for patients with melanoma.…”

Predicting circulating biomarker response and its impact on the survival of advanced melanoma patients treated with adjuvant therapy

“…Although it has been demonstrated that these targeted drugs significantly improve PFS and OS in comparison with chemotherapy, the patients receiving this treatment rapidly develop resistance 16 . On the other hand, the FDA-approved checkpoint inhibitors against cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death 1 (PD-1) enhance the natural antitumor immune response of the patients and also lead to improved survival 17 . However, only a subset of patients respond to immune checkpoint inhibitors and resistance mechanisms can also arise among this group of responders.…”

Extracranial systemic antitumor response through the abscopal effect induced by brain radiation in a patient with metastatic melanoma

“…Thus, radiation therapy boosts the systemic antitumor response of the immunotherapy and enhances the probability of abscopal effects in the treatment of malignant cancers, More recent advances in the development of molecularly targeted agents have dramatically shifted the landscape of the treatment of metastatic melanoma with improved longer survival outcomes [30][31][32]. The introduction of novel immune modulators such as cytotoxic T-lymphocyte antigen-4 (CTLA4) and programmed death-1 (PD-1)/programmed death ligand-1 (PDL-1) based treatments and VEGF inhibitors have been an integral part of the immunogenic tumors such as melanoma https://doi.org/10.3857/roj.2019.00437 [33,34]. Nivolumab is a fully human immunoglobulin G4 immune checkpoint inhibitor antibody that targets PD-1 and promotes antitumor immunity.…”