PD1 Checkpoint Blockade in Melanoma: From Monotherapy to Combination Therapies

Abstract

Malignant melanoma is a highly aggressive tumor due to its early metastatic spread. For decades, the median survival for patients with advanced metastatic disease treated with standard chemotherapy was only 6–12 months. During this time, substantial evidences have been accumulated demonstrating that cytotoxic CD8⁺ T lymphocytes have the capability to specifically recognize and kill autologous melanoma cells. However, attempts to therapeutically exploit this knowledge have long been of limited success, due to the fact that the complex regulation of T cell activity in the tumor microenvironment was poorly understood. T cells infiltrating melanoma metastases become activated upon T cell receptor-dependent recognition of cognate antigens on melanoma cells. But at the same time, T cells receive inhibitory signals via their co-receptor PD1 that engages its ligand PD-L1 on melanoma cells. Thus, by acquisition of PD-L1 surface expression, melanoma cells dampen the T cell’s activity. The clinical implementation of antibodies targeting the immune-regulatory PD1/PD-L1 axis, thereby releasing T cells from the PD1 checkpoint, was a breakthrough in melanoma immunotherapy. Around 30–40% of melanoma patients respond to anti-PD1 monotherapy. Response rates could even be enhanced to 50% by the combination of antibodies targeting PD1 and CTLA4 another inhibitory checkpoint of T cell activation. However, combination therapy is less well tolerated causing severe side effects. Thus, PD1 is currently tested in combination with other agents that might have an improved safety profile and induce clinical responses also in those patients that at present do not respond to anti-PD1 monotherapy.