2016. is focused on overcoming barriers to efficacy via rational combinations that overcome resistance to therapy. expanded T cells and chimeric antigen receptor T cells (CAR-T)). CHECKPOINT BLOCKADE Rationale Checkpoint molecules, such as cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and programmed cell TSPAN32 death-1 (PD-1), are key players in the physiological regulation of T cell activation and expansion. Inhibition of these pathways has been extensively investigated as potential target for treatment of various malignancies. The binding of B7-1 and B7-2 molecules (also known as CD80 and CD86) on antigen presenting cells to the Torcetrapib (CP-529414) CD28 molecule expressed on the surface of T cells is a critical step for lymphocyte activation(17). The CTLA-4 molecule, which is also expressed by T cells, competes with CD28 for binding of B7-1 or B7-2 but leads, in contrast, to inhibition of T cell activation(18). Another important inhibitory axis involves PD-1/PD-L1(19). The interaction of PD-1, which is expressed on T cells, with its ligands, programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 (PD-L2), which are expressed on antigen presenting cells, also causes inhibition of T cell receptor Torcetrapib (CP-529414) signaling resulting in Torcetrapib (CP-529414) decreased antitumor immune responses while nurturing the survival of tumor cells(20). The PD-1 pathway appears to be an important mechanism in the HL microenvironment. PD-1 expression is increased in tumor infiltrating lymphocytes as well as peripheral T cells in HL patients and may be one mechanism that contributes to the inhibitory HL microenvironment and inability of T cells to destroy HRS cells(21). In addition, increased expression of PD-1 on tumor-infiltrating lymphocytes in HL has been associated with decreased overall survival (OS) in patients independent of disease stage(22). HRS cells consistently express high levels of PD-L1 and PD-L2(21, 23-26), further providing a rationale for the success of PD-1 inhibition in HL. studies confirmed that blockade of the PD-1 signaling cascade with anti-PD-1 antibodies restores the function of tumor infiltrating lymphocytes, suggesting that targeting this pathway should prove beneficial(21). Expression of PD-L1 and PD-L2 on HRS cells is Torcetrapib (CP-529414) induced via amplification of the chromosomal region 9p24.1, where the genes encoding both PD-L1 and PD-L2 are located(23). In addition, the 9p24.1 amplification region includes the JAK2 locus, leading to increased JAK/STAT signaling further enhancing transcription of PD-L1(23). Some patients with classical HL have normal 9p24.1 copy number, yet they still have increased PD-L1 expression. Another etiology for increased PD-L1 expression in classical HL is attributed to Epstein Barr Virus (EBV) infection in HRS cells(24), present in about 40% of patients with HL, with results varying across different population groups(27). In the cases of EBV+ HL, the EBV-associated latent membrane protein-1 (LMP-1) mediates the activation of the JAK-STAT and activator protein-1 pathways, leading to increased PD-L1 expression(24). In addition to being expressed on HRS cells, PD-L1 can be found on tumor-infiltrating macrophages in the tumor microenvironment, further contributing to the ineffectiveness of T cells in eradicating HRS cells(26). This may be a contributing factor to previous reports describing an association between increased number of tumor associated macrophages and poor outcome in HL(12). The anti-CTLA-4 monoclonal antibody, ipilimumab, was the first checkpoint inhibitor approved for cancer therapy, but there have been limited studies of this therapy in HL, largely due to its increased toxicity compared to PD-1 inhibitors. In addition, the high importance of the PD-1/PD-L1 axis in classical HL makes this pathway an excellent therapeutic target. Recently, two PD-1 inhibitors, nivolumab and pembrolizumab, have shown great success for treatment of relapsed or refractory HL and have been FDA approved for this indication. Ipilimumab There have been limited studies of ipilimumab, the CTLA-4 inhibitor, in HL. Ipilimumab was evaluated in patients with relapsed hematologic malignancies post alloSCT with the goal of increasing graft versus tumor effect. In a phase 1 study, 14 patients with relapsed HL post alloSCT were treated with a single dose of ipilimumab (with the option of redosing if progression occurred after initial response) with 2 patients showing a complete response (CR)(28). In a follow up study again looking at relapsed hematologic.