BRAF targets in melanoma. Biological mechanisms, resistance, and drug discovery. Cancer drug discovery and development. Volume 82. Ed. Ryan J. Sullivan. Springer (2015)
Another immune checkpoint, programmed death 1 (PD-1), acts as an inhibitory receptor of T cells similar to CTLA-4. However, in contrast to CTLA4, the ligand for PD-1 (PDL1) appears to be expressed almost exclusively at sites of inflammation, such as in the tumor microenvironment. This observation has raised the hope that blockade of PD1 binding with PDL1 might lead to more selective restoration of immunity within the tumor microenvironment and, therefore, less associated toxicity than seen with CTLA4 blockade. Early clinical trials investigating antibodies to PD-1 and PDL1 in patients with melanoma have shown response rates ranging from 25–50% [103, 104]. In addition a study evaluating the concurrent administration of the combination of ipilimumab and the PD1 antibody nivolumab produced rapid and deep tumor responses in patients with metastatic melanoma and an overall response rate of 53% in a small number of patients (103). The promising results seen with various anti-PD1 and PDL1 antibodies either alone or in combination with ipilimumab have led to multiple randomized clinical trials of comparing anti-PD-1 antibodies alone or in combination with ipilimumab to standard of care in patients metastatic melanoma. In addition, efforts are underway to study the optimal coordination of immunotherapy with molecularly targeted therapies in patients with BRAF mutant melanomas.
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