*2.3.1 Ipilimumab*

In contrast to the wild application of anti-PD-1/PD-L1 inhibitor for the treatment of HL, very few studies have been conducted to assess the efficacy of anti-CTLA-4

#### *Immune Checkpoint Inhibitors in Hodgkin Lymphoma and Non-Hodgkin Lymphoma DOI: http://dx.doi.org/10.5772/intechopen.107435*

inhibitor against HL. Ipilimumab is a fully humanized anti-CTLA-4 IgG1κ monoclonal antibody. Although several clinical trials of ipilimumab have been conducted for numerous solid tumors [107–110], and there are some ongoing clinical trials assessing the possibility of using ipilimumab in r/r cHL (like NCT04938232); currently very few reports have demonstrated the efficacy of ipilimumab as monotherapy in the treatment of HL. Bashey et al*.* reported that two out of 14 relapsed HL patients after allo-HSCT achieved CR upon ipilimumab treatment [111]. In comparison, the possibility of co-administrating ipilimumab with other agents against HL has been evaluated.

#### *2.3.1.1 Combined therapy*

In an open-label, multicenter, phase I trial assessing the efficacy of combination therapy in 61 patients with r/r HL (NCT01896999), patients were divided into three groups: combinations of brentuximab vedotin with ipilimumab (ipi-group) or nivolumab (nivo-group) or both (triplet-group) [112]. Although the overall response rates were similar for all three groups (76% for ipi-group, 89% for nivo-group, and 82% for triplet-group), triplet groups demonstrated a higher CR rate (73%), as compared with ipi- (57%) and nivo-groups (61%). These are also higher than the expected individual monotherapies. However, the inclusion of ipilimumab in the combination therapy significantly increased the chance of severe (grade 3 or 4) treatment-related AEs, with 43% in the ipi-group and 50% in the triplet-group. On contrary, this number is only 16% in the nivo-group. This may raise concerns for the possible higher toxicity of ipilimumab in treating Hodgkin lymphoma.

Lenalidomide is an FDA-approved drug for the treatment of multiple myeloma, with the ability of modulating cellular and humoral immunity and antiangiogenesis [113]. In a phase I dose-escalation study of ipilimumab and lenalidomide including seven refractory HL patients (NCT01750983) [114], PR was observed in one patient, and three patients experienced tumor shrinkage (less than PR).

#### **2.4 Other potential immune checkpoint inhibitors**

Besides the well-known immune checkpoints PD-1 and CTLA-4, novel immune checkpoints may be used as therapeutic targets for the treatment of HL. Halabi et al*.* found that lymphocyte-activation gene 3 (LAG-3) and T-cell immunoglobulin and mucin-domain containing 3 (TIM-3) are almost constitutively expressed in cHL [115]. Therefore, clinical trials targeting LAG-3 (relatlimab, NCT02061761) or TIM-3 (BMS-986258, NCT03446040) alone or in combination with nivolumab in the treatment of r/r HL are completed, and results will be released soon. In addition, T-cell Ig and ITIM domains (TIGIT) are another immune checkpoint receptor that is found to be highly co-expressed with PD-1 in r/r cHL patients [116]. Therefore, co-inhibition of PD-1 and TIGIT could be a novel strategy for treating r/r cHL.

Immune checkpoints are expressed in immune cells other than T cells, which could be targeted as well. In a phase Ib study, Armand et al*.* evaluated the efficacy and safety of dual inhibition of PD-1 and CTLA-4 (65 patients) or killer immunoglobulinlike receptors (KIRs) (72 patients) for r/r cHL [117]. KIR is expressed on NK cells and inhibits their function by interacting with MHC I [118]. However, the authors reported that the combination failed to further improve the efficacy, as compared with nivolumab monotherapy.
