Beyond CTLA-4 and PD-1 Inhibition: Novel Immune Checkpoint Molecules for Melanoma Treatment

• Published in: Cancers Vol. 15; no. 10; p. 2718
• Main Authors: Ziogas, Dimitrios C., Theocharopoulos, Charalampos, Lialios, Panagiotis-Petros, Foteinou, Dimitra, Koumprentziotis, Ioannis-Alexios, Xynos, Georgios, Gogas, Helen
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 11.05.2023; MDPI
• Subjects: Antigens; Biological products; BTLA protein; Cancer; Care and treatment; CD223 antigen; CD27 antigen; CD70 antigen; CTLA-4 protein; Cytokines; Drug therapy; Early experience; Effector cells; FDA approval; Health aspects; Immune checkpoint inhibitors; Immune response; Immunoglobulins; Immunomodulation; Ipilimumab; Kinases; Ligands; Lymphocytes; Lymphocytes T; Melanoma; Metastases; Metastasis; Patients; PD-1 protein; Peptides; Prognosis; Receptor mechanisms; Review; Signal transduction; T cells; Tumors; relatlimab; VISTA; LAG-3; immunotherapy resistance; melanoma; immune checkpoint inhibitors; TIGIT; TIM-3; immune checkpoints
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers15102718

More than ten years after the approval of ipilimumab, immune checkpoint inhibitors (ICIs) against PD-1 and CTLA-4 have been established as the most effective treatment for locally advanced or metastatic melanoma, achieving durable responses either as monotherapies or in combinatorial regimens. However, a considerable proportion of patients do not respond or experience early relapse, due to multiple parameters that contribute to melanoma resistance. The expression of other immune checkpoints beyond the PD-1 and CTLA-4 molecules remains a major mechanism of immune evasion. The recent approval of anti-LAG-3 ICI, relatlimab, in combination with nivolumab for metastatic disease, has capitalized on the extensive research in the field and has highlighted the potential for further improvement of melanoma prognosis by synergistically blocking additional immune targets with new ICI-doublets, antibody–drug conjugates, or other novel modalities. Herein, we provide a comprehensive overview of presently published immune checkpoint molecules, including LAG-3, TIGIT, TIM-3, VISTA, IDO1/IDO2/TDO, CD27/CD70, CD39/73, HVEM/BTLA/CD160 and B7-H3. Beginning from their immunomodulatory properties as co-inhibitory or co-stimulatory receptors, we present all therapeutic modalities targeting these molecules that have been tested in melanoma treatment either in preclinical or clinical settings. Better understanding of the checkpoint-mediated crosstalk between melanoma and immune effector cells is essential for generating more effective strategies with augmented immune response.