For example, targeting of either CD28, PD-1, PD-L1, or CTLA-4 has been investigated and some therapies targeting this machinery are already in clinical use (e.g., the anti-CTLA-4 antibody Ipilimumab for the treatment of advanced metastatic melanoma, and the anti-PD-1 antibodies Pembrolizumab and Nivolumab for the treatment of advanced melanoma, advanced non-small cell lung cancer, and metastatic renal cell carcinoma) (Dilek et al., 2013). The gene discussed is CD28; the disease is metastatic melanoma.