*2.1.4 Tislelizumab*

Tislelizumab is a specially engineered humanized anti-PD-1 IgG4 monoclonal antibody. In contrast to other conventional PD-1 inhibitors, the Fcγ receptor (FcɤR) fragment of tislelizumab was modified to minimize the binding of macrophages and the subsequent antibody-dependent phagocytosis. The antibody-dependent phagocytosis by macrophages could potentially lead to T-cell clearance and greatly affect the efficacy of anti-PD-1 therapy [90]. Therefore, the FcɤR modification allows tislelizumab to exhibit improved anti-tumor function. In the single-arm, multicenter, phase II trial of tislelizumab in patients with r/r cHL (NCT03209973) [91], 61 of 70

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

(87.1%) patients achieved an objective response, including a high CR rate of 62.9% (44 of 70). The estimated median 9-month PFS was 74.5%. AEs were observed in 65 of 70 (92.9%) patients, with 15 (21.4%) experiencing grade 3 or 4 AEs.

#### *2.1.4.1 Combined therapy.*

Similar to other anti-PD-1 antibodies, co-administration of low-dose decitabine and tislelizumab for the treatment of r/r cHL has been reported. A 27-year-old male r/r cHL patient who failed eight lines of therapy (including PD-1 inhibition) achieved partial remission upon receiving decitabine plus tislelizumab treatment. No disease progression was observed during the entire 11.5 months of follow-up [92].

#### *2.1.5 Zimberelimab*

Zimberelimab (GLS-010) is the first fully human anti-PD-1 monoclonal antibody produced in a transgenic rat platform. While sharing the same heavy chain constant region as nivolumab and pembrolizumab, zimberelimab has two different modifications, namely S228P and N95S, in IgG4 core-hinge area and CDR3 area of the light chain, respectively. The S228P mutation prevents Fab-arm exchange, and the N95S mutation prevents the glycosylation of the antigen-binding domain [93]. Phase I studies for advanced solid tumors [94, 95] or preliminary studies for r/r cHL [96] have suggested high efficacy and acceptable safety. In a phase II trial for patients with r/r cHL (NCT03655483), 77 of 85 (90.6%) patients had objective responses, with a CR rate of 32.9% (28 patients). Twelve-month PFS and OS were 78% and 99%, respectively. Treatment-related AEs were found in 79 of 85 (92.9%) patients, with 24 (28.2%) of them demonstrated grade 3 or 4 and 1 exhibited grade 5 treatment-related AE (gastrointestinal infection) [93].

#### *2.1.6 Penpulimab*

Penpulimab is a humanized anti-PD-1 monoclonal antibody co-developed by Akeso Biopharma and Chia Tai Tianqing for the treatment of solid tumors. Similar to tislelizumab, the FcɤR fragment region of penpulimab is engineered, through which the FcɤR bindings of effectors (such as macrophages) are eliminated. As the results, T cells are protected from antibody-dependent cell-mediated cytotoxicity (ADCC), and the efficacy of tislelizumab is expected to be enhanced. In the open-label, multicenter, single-arm, phase I/II study (NCT03722147), the objective response rate was 89.4% (76 of 85 patients), with 40 (47.1%) patients achieving CR. Twelve-month PFS was 72.1%. Treatment-related AEs were observed in 97.9% (92 of 94) patients, with 25 (26.6%) experienced grade 3 or above treatment-related AEs [97, 98].

#### **2.2 Anti-PD-L1 checkpoint inhibitors**

Besides PD-1 blockade, targeting PD-L1 is an alternative strategy to avoid PD-1/ PD-L1 immune checkpoints. However, it should be noted that PD-L1 and PD-L2, the two ligands to PD-1, are differentially expressed in the tumor microenvironment of cHL [29, 99]. Therefore, anti-PD-L1 monotherapy may be not sufficient to completely inhibit the PD-1 pathway, its efficacy may be lower than PD-1 inhibition alone. The use of PD-L1 inhibitors in HL should be carefully evaluated.

### *2.2.1 Avelumab*

Avelumab (MSB0010718C) is a human anti-PD-L1 IgG1 monoclonal antibody. Besides blocking PD-1/PD-L1 interactions, the binding of avelumab on tumor cells induces ADCC via the FcɤR binding [100, 101]. Unlike the ADCC induced by anti-PD-1 antibodies that impair T-cell function and dampen the efficacy of treatment, the ADCC induced by anti-PD-L1 antibodies provides another mechanism of tumor clearance and further enhances treatment efficacy. In a phase Ib trial of avelumab against r/r cHL [102], 13 of 31 (41.2%) patients showed an objective response, with six (19.4%) achieving CR and seven (22.6%) achieved PR. Twelve-month PFS was 18.2%, and the median PFS was 5.7 months. Treatment-related AEs were observed in 26 (86.7%) patients and 13 (43.3%) of them are grade 3 or 4.

#### *2.2.2 Sugemalimab*

Sugemalimab is a fully human, full-length, anti-PD-L1 IgG4 monoclonal antibody developed by CStone Pharmaceuticals for advanced solid tumors and lymphoma. In 2021, it has been approved in China for the first-line treatment of various forms of non-smallcell lung cancer in combination with different treatments. Phase Ia and Ib studies have been finished for sugemalimab against advanced malignancies (including 5 cHL patients in phase Ia study) [103]. They have demonstrated the safety and anti-tumor efficacy of sugemalimab. Currently, a single-arm, phase 2 trial of sugemalimab against r/r cHL (as monotherapy) is underway (NCT03505996) and has enrolled 80 patients [104].

### *2.2.3 Durvalumab*

Durvalumab is another human anti-PD-L1 monoclonal antibody and has been approved by US FDA for urothelial carcinoma and stage III non-small-cell lung cancer [105]. Ogasawara et al*.* have conducted a pharmacokinetic analysis of durvalumab in 267 patients with hematological malignancies (including HL) [105]. They suggested the dosing regimen (1500 mg every 4 weeks) for hematologic malignancies can be the same as other solid tumors. This suggests a potential application of durvalumab against HL.

#### *2.2.4 Atezolizumab*

Atezolizumab is an inhibitor of PD-L1, and it has been approved by the US FDA and the European Medicines Agency for certain forms of solid tumors (such as triplenegative breast cancer or non-small-cell lung carcinoma, as monotherapy or used in combination) [106]. iMATRIX was a multicenter, open-label, phase I/II trial of young patients (<30 years old) with solid tumors or lymphomas (including nine HL patients, NCT02541604) [106]. Unfortunately, only two patients demonstrated objective response (PR). For the rest of the HL patients, two of them remained with stable disease, and five suffered from disease progression. Another phase II clinical trial of atezolizumab in r/r HL (NCT03120676) was also terminated due to lack of accrual.
