*3.1.3 Epstein-Barr virus (EBV)+ diffuse large B-cell lymphoma (DLBCL) and primary DLBCL of the central nervous system (PCNSL)*

Epstein-Barr virus (EBV) is detected in a variety of B-cell lymphomas (BCLs) and lymphoproliferative disorders (B-LPD) with poor prognosis, associated with immunodeficiency, a key factor of lymphomagenesis. EBV+ DLBCL-NOS was first described as age-related EBV-associated LPD in 2003 with poor outcomes compared with EBV-negative DLBCL patients [146]. Unfortunately, the biology of EBV+ DLBCL-NOS remains unsure, and no standard approaches for these kinds of patients. Researchers have identified that 100% PD-L1 expression was seen in EBV+ DLBCL in a larger cohort study (*n* = 1100), which was significantly associated with EBV+ status [147, 148]. Liu et al*.* have identified that anti-PD-1 antibodies can restore and active function of T cells in EBV+ DLBCL [149]. Thus, the PD-L1/PD-1 pathway may be a potential therapeutic target for EBV+ DLBCL. Many studies are ongoing to assess the application of ICIs combined with chemotherapies in EBV+ DLBCL (e.g., NCT03212807, NCT04181489, NCT04705129, and so on).

Also, primary central nervous lymphoma (PCNSL) is a rare extra-nodal lymphoma with a high refractory/relapse rate using high-dose MTX-based treatment [150, 151]. For relapsed/refractory PCNSL (r/r PCNSL), new strategies have been explored including immunotherapy. PD-1 antibodies in r/r PCNSL have been reported with good efficacy in some case reports [152, 153]. Thus, some retrospective and prospective studies discussed the efficacy of anti-PD-1 antibody as monotherapy and in combination with other drugs [153, 154]. Unluckily, the results of ICIs in r/r PCNSL varied. Especially, we have seen promising efficacy in PCNSL with Bruton's Tyrosine Kinase and Immune Modulatory Small Molecules. Some explorations of ICIs in primary and r/r PCNSL are under study, especially for those who have higher PD-L1 expression and no chance to do MTX-based chemotherapy (NCT04899427, NCT05425654, and NCT04831658).

In other B-NHL entities, the rates of PD-L1 expression on neoplastic B cells are low: ∼5% in FL, ∼10% in high-grade MZL, and 0% in MCL. Therefore, slightly rare studies have been explored in these types of B-NHL.

#### **3.2 Immune checkpoints inhibitors in T-non-Hodgkin lymphoma**

PD-1 or PD-L1 has been used in various kinds of NHLs, either alone or in combination with other agents, which have promising results in some Lymphoma. For T-cell lymphomas, this strategy has been challenging because these markers may be expressed on the tumor cells themselves resulting in inadvertent tumor growth.

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

Peripheral T-cell lymphoma (PTCL) is a group of lymphoproliferative disorders, originating from mature T/NK cells with highly heterogeneous, aggressive characteristics and poor prognosis. There are 27 subtypes of PTCL in the World Health Organization 2016 classification of lymphoid neoplasm, including extranodal NK/Tcell lymphoma, nasal-type (ENKTL), nonspecific (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), and anaplastic lymphoma kinase (ALK)+/− anaplastic large cell lymphoma (ALCL) [155, 156]. CHOP-based regimens are the first-line treatments for PTCL other than NK/T-cell lymphoma, but the efficacy is limited [157, 158]. Thus, effective treatments for relapsed or refractory (r/r) PTCL are urgently needed. PD-1 and PD-L1 expression is commonly observed in PTCL cells, and PD-1 or PD-L1 is considered a prognostic biomarker and target. A phase I study (five patients with r/r PTCL) and phase 2 study (12 patients with r/r PTCL) have identified the clinical value of Nivolumab in r/r PTCL patients with 33% ORR [159, 160]. Also, the promising results using pembrolizumab have been seen in seven relapsed ENKT lymphoma with 100% overall response rates after a median of 7 weeks of treatment, either EBV DNA-positive or negative. The remission has been maintained at a median follow-up of 6 months. Similar results were reported for nivolumab. Thus, several studies are ongoing to explore the efficacy of PD-1 inhibitors in the treatment of ENKL. Studies showed that the response is correlated with the level of PD-1 expression, especially in EBV DNA positive patients. Although, studies were halted early due to the short duration of response and concern for hyperprogression. Encouraging results were also seen with pembrolizumab in patients with r/r cutaneous T-cell lymphoma with 38% ORR in a phase 2 study [142]. There was an alarming report of hyperprogression in three patients with ATLL that were enrolled in the nivolumab trial. Clinical progression was also accompanied by an increase in the viral load [143]. In these cases, PD-1 tumor suppressor function may have been lifted by PD-1 blockade. The use of PD-1 and PD-L1 antibodies in ATLL has to be viewed with caution. Therefore, more clinical trials should be done to evaluate the efficacy and safety of ICIs in different subtypes of PTCL.

Ipilimumab, an inhibitor of CTLA-4 (also known as CD152), provides both positive and negative feedback for T-cell activation when combined with its costimulatory receptor CD28. But the effect of CTLA-4 inhibitors in PTCL is not well characterized. In general, immunotherapy for PTCL is promising. For other immune checkpoint proteins, such as TIGIT, TIM-3, and LAG-3, their evaluation in PTCL is still at the preclinical stage and needed to be further explored via relevant clinical trials. Some studies have shown that the combined blockade of the TIM-3 and PD-1 pathways has significant efficacy in hematological tumors [161]. More importantly, the combination of PD-1/PD-L1 inhibitors and CAR-T cell therapy are worthy of exploring [162]. These ICIs combined therapies may be the best strategy for tumor therapy and promote the prognosis in near future.
