**3. Immune checkpoints inhibitors in non-Hodgkin lymphoma**

Non-Hodgkin lymphoma (NHL) is a mostly common and heterogeneous group of lymphomas derived from B and T lymphocytes, natural killer (NK), cells or precursors of these cells. Its pathology remains largely unexplained. Recent studies identified that tumor microenvironment (TME) in NHL is now playing a significant role in immune suppression and propagating tumor growth [119, 120]. Therefore, immunotherapies have been widely used and investigated in NHL to enhance or manipulate host anti-tumor immunity. In recent years, interference of PD-1/PD-L1 signaling, the immune checkpoint (therefore also known as checkpoint blockade), has been used in these kinds of lymphomas for its clinical efficacy by enhancing anti-tumor immune response. More importantly, therapeutic interference of checkpoint blockade has enjoyed significant success in cHL, but clinical response greatly varied in NHLs [121].

PD-1 and its ligands (PD-Ls), PD-L1 (also known as CD274 or B7-H1) and PD-L2 (as known as CD273 or B7-DC), form a signaling network that serves as a checkpoint to limit T-cell immunity, causing T-cell exhaustion [6, 122, 123]. Targeting PD-1 signaling to block T-cell activity with immune inhibitory antibodies can promote the activation, maturation, and proliferation of T-cells, eventually regulating antitumor activity, which has been investigated in NHL. Recent studies suggested that ICIs have been considered a promising and effective treatment strategy for some types of NHLs. Thus, PD-1 antibodies have been approved by the US FDA including nivolumab and pembrolizumab. Now, let us review the effectiveness of ICIs in NHL.

#### **3.1 Immune checkpoints inhibitors in B-non-Hodgkin lymphoma**

#### *3.1.1 Diffuse large B-cell lymphoma (DLBCL)*

Diffuse large B-cell lymphoma (DLBCL) represents 30–40% of all non-Hodgkin lymphomas (NHL) with a 60–70% curable rate in Rituximab Era [120]. However, about one-third of these patients are refractory or resistant to standard treatment. In addition, there are several subtypes of DLBCL in the 2016 World Health Organization (WHO) classification of lymphoid malignancies according to unique clinical and pathological features, including primary DLBCL of the central nervous system (PCNSL), primary cutaneous DLBCL, leg type, T-cell/histiocyte-rich large cell lymphoma, and EBV positive DLBCL of the elderly [124]. Nevertheless, most cases of DLBCL fall into the "not otherwise specified" (NOS) category [125]. As we know, immune evasion plays an important pathogenetic mechanism in DLBCL evolution, and immune checkpoint blockade therapy was explored in all kinds of lymphomas. But the outcome of immunotherapy remained controversial.

PD-L1 expression in DLBCL, with an incidence of ~25%, is associated with inferior outcomes, involving in DLBCL pathogenesis, which is considered a potential target [126, 127]. Importantly, chromosome 9p24.1 copy number alteration observed in DLBCL, in addition to cHL, is also involved in negative T cell regulation and NF-κb signaling pathway, which is associated with responsiveness to ICIs in relapsed/refractory DLBCL (r/r DLBCL) [126]. However, the results of ICIs in r/r DLBCL are disappointing [128, 129]. A phase I study to evaluate the safety and efficacy of nivolumab enrolled 81 r/r lymphoma patients (11 DLBCL) and showed an ORR of 36% in DLBCL. A recent phase II study (NCT02038933) showed that nivolumab monotherapy had good safety profiles but low ORR in DLBCL patients [130]. However, clinical trials of nivolumab combined with other immunochemotherapies are still in progress.

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

Pembrolizumab (Keytruda), a humanized anti-PD-1 MoAb with excellent anti-tumor activity, was explored in DLBCL. This study including 30 DLBCL patients, evaluated the efficacy of pembrolizumab (200mg) with R-CHOP, and showed a 90% ORR, 77% CR, and 83% 2y-PFS at a median follow-up of 25.5 months, suggesting that this combination may be a promising treatment strategy [131]. All in all, the results of anti-PD-1 antibody in DLBCL patients are not promising in the current clinical trials, and anti-PD-1 antibody combination therapy is also under investigation [126].

It is a worthy note that anti-PD-L1 antibody atezolizumab (MPDL-3280A) combined chemotherapy seems a promising approach in DLBCL. In a phase I/II study, atezolizumab-R-CHOP for DLBCL demonstrated high efficacy (ORR of 87.5%) and durable responses (24 months for 80% of patients) for the combinational group [132]. Fifty-eight DLBCL patients enrolled in the study to assess the anti-tumor activity of atezolizumab associated with Venetolax (a BCL-2 inhibitor) and Obinutuzumab with 23.6% ORR (NCT03276468). In another phase 1/2 study, atezolizumab in combination with rituximab and polatuzumab in 21 participants with r/r DLBCL showed 57.14% ORR and 33.33% CR. In additional, atezolizumab with mosunetuzumab (a bispecific CD20-CD3 monoclonal antibody) was evaluated (NCT02500407). Certainly, anti-PD-L1 antibodies have been extensively investigated in combination with new-generation CD20 antibodies (NCT03533283), Chimeric antigen receptor (CAR)-T (NCT02926833), and ASCT (NCT02362997).

Durvalumab, another humanized IgG1-kappa monoclonal antibody against PD-L1, showed markedly anti-tumor activity in vivo. Thus, like atezolizumab, numbers of clinical trials are ongoing to investigate the value of durvalumab as a single agent or in combination with other treatment approaches or CAR T-cells in B-NHL patients. Encouraging results were commonly seen in patients treated with durvalumab in combination therapy in early studies. Durvalumab with Ibrutinib in DLBCL has 25% ORR and 4.6 months PFS [133]. Also, durvalumab combined with R-CHOP showed 54.10% CR but 51% serious AEs [134]. More interesting, remarkable results were found when combined with durvalumab and CAR T-cells in B-NHL including 12 DLBCLs, 2 high-grade B-cell lymphomas, and 1 PMBL (NCT03310619 (PLATFORM) and NCT02706405), which reported an ORR of 91%, including 64% CR [135, 136]. From these clinical results, AEs were frequently seen in combination therapy, which needed to be noted [137, 138].

Another inhibitor signaling of CTLA-4 including ipilimumab was not explored for its efficacy and safety. Recently, the combination of ipilimumab and nivolumab in patients with high-risk DLBCL after Allo-SCT has been opened (NCT02681302) [139]. More results should be worthy of expectation.

#### *3.1.2 Primary mediastinal large B-cell lymphoma (PMBCL)*

Importantly, anti-PD-1 MoAb has promising results in some special DLBCL. Primary mediastinal large B-cell lymphoma (PMBCL) comprises approximately 10% of DLBCL with different clinicopathologic and molecular signature, which have a good prognosis with R-CHOP/R-DAEPOCH combined with radiotherapy, with a 5-year event-free survival rate of 93% and OS rate of 97% [140]. However, more than 10% of patients still suffered relapsed or refractory, and the outcomes in r/r PMBCL remain poor. Studies have elucidated that PMBCL shared many similar biological features with cHL, including the importance of JAK-STAT and NF-κB signaling pathways as well as immune evasion [141]. Aberration expressions of PD-L1 and PD-L2 were found in PMBCL tumors, and the efficacy of anti-PD-1 antibody (pembrolizumab)

in r/r PMBCL was confirmed in phase 1 KEYNOTE-013 study [142]. Subsequently, a phase 2 study (KEYNOTE-170) has evaluated the efficacy of pembrolizumab in r/r PMBCL, and similar results were observed, with 45% ORR, and 13% CR, and median duration of response (DOR) not yet reached [143]. Thus, pembrolizumab has been approved in r/r PMBCL by FDA. After that, ICIs combined with other therapeutic agents for r/r PMBCL have been widely studied all over the world. Nivolumab combined with the anti-CD30 antibody-drug conjugate (ADC) brentuximab vedotin (BV) has been studied for r/r PMBCL in the CheckMate 436 study with an ORR was 73% and CR 37% [144]. These studies have identified the efficacy of PD-1 in PMBCL, especially combined with other agents. Numerous clinical trials assessing combination therapies with immune checkpoint inhibitors are ongoing [145].
