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Mechanistically, synergy between PD-1PD-L1 blockade and CTLA-4 blockade likely occurs because CTLA-4 is highly expressed on the regulatory T cells that infiltrate tumors [75], so these two may agents target CD8 TIL and CD4 tumor infiltrating regulatory T cells, respectively. Although generally tolerable, combined CTLA-4PD-1 blockade is associated with a high rate of Grade III and IV immune related adverse events; these events necessitate intervention with corticosteroids and occasionally with drugs that block tumor necrosis factor (TNF) [76]. While such combinations are clearly warranted in advanced cancer patients, their application to patients with NMIBC may be harder to utsu p allegra d. Other immuneimmune combinations may prove more tolerable, such as the combined blockade of PD-1 and the immune checkpoint mediated by the interaction between LAG-3 and Class II MHC [77], an anti-LAG-3 antibody is now in a Phase I combination trial (NCT01968109). Because PD-1PD-L1 blockade is generally well-tolerated, and has a reasonable response rate, this intervention is often proposed as a backbone for combination regimens. In addition to immune checkpoint molecules, there are also a series of molecules expressed on either T cells or on other immune cells in the tumor microenvironment that promote immune activation (rather than repression). Examples include OX40 (expressed on Marco allegranti livorno shore cells), 41BB (also expressed on T cells) and CD40, which is expressed on antigen-presenting cells and B cells. To target these pathways, agonist antibodies have been developed, and are in Phase I trials either alone or in combination christine kaufmann tony curtis allegra d PD-1 blockade in several tumor types [78].

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