Review Article Selection of New Immunotherapy Targets for NK/T Cell Lymphoma

Am J Transl Res 2020;12(11):7034-7047 www.ajtr.org /ISSN:1943-8141/AJTR0115722

Review Article Selection of new immunotherapy targets for NK/T cell lymphoma

Kebing Lv, Xin Li, Hui Yu, Xinfeng Chen, Mingzhi Zhang, Xiaolong Wu

Department of Oncology, Zhengzhou University First Affiliated Hospital, Lymphoma Diagnosis and Treatment Center of Henan Province, No. 1 Jianshe East Road, Zhengzhou, Henan, China Received June 5, 2020; Accepted October 8, 2020; Epub November 15, 2020; Published November 30, 2020

Abstract: Extranodal NK/T cell lymphoma, nasal type, is a rare type of non-Hodgkin’s lymphoma (NHL), and the aetiology is not fully understood. Although the clinical outcome of anthracycline-based chemotherapy was dismal because of multidrug resistance (MDR). Novel therapeutic strategies including L-asparaginase-containing regimens, radiotherapy, sequential chemotherapy and radiotherapy, and concurrent chemoradiotherapy (CCRT) have remark- ably improved outcomes. However, the overall survival (OS) rate of advanced stage patients is not satisfactory compared with patients with non-advanced-stage disease. Immunotherapy is a promising treatment for ENKTCL. Indeed, it has been proven that targeted therapies such as anti-CD30 antibodies and naked anti-CD38 antibodies are effective. In addition to these therapies that target cell surface antigens, therapies targeting intracellular signalling pathways and the microenvironment are considerably beneficial. EBV-driven overexpression of latent membrane proteins [LMP1 and LMP2] activates the pro-proliferation NF-κB/MAPK signalling pathway and leads to high PD-L1 expression. Binding of PD-L1 to PD-1 expressing cytotoxic T cells causes apoptosis and inactivation of T lymphocytes, achieving immune escape. On the basis of this mechanism, a variety of small molecular inhibitors, such as anti-PD-1 antibodies, NF-κB inhibitors, EBV antigens, and LMP1 and LMP2 antigens, can be applied. Via another signalling pathway the JAK/STAT pathway, upregulation and activation and mutation of genes promotes proliferation and ENKTCL lymphomagenesis, and JAK inhibitors have thus been applied. This article reviews recent advances in ENKTCL immunotherapy as a promising treatment for this fatal disease.

Keywords: NK/T cell lymphoma, immunotherapy, targets

Background middle-aged people, with a higher incidence in males than in females. It has been speculated Extranodal natural killer/T cell lymphoma (EN- that EBV infection in childhood and pesticides KTCL) is an aggressive haematological malig- may be risk factors [4]. nancy that is frequently found in the upper aerodigestive tract but can involve non-nasal sites, Known mutations associated with ENKTCL, such as the gastrointestinal tract, skin, soft tis- such as gene amplification, deletion and muta- sue and testis. Its incidence in Asia and South tion including in cell cycle regulators Rb, TP53, America is approximately 10%, though it is as PRDM1, CDKN and FOXO3, are shared with low as 1% in North America and Western other subtypes of lymphoma, with no specificity Europe [1]. According to Chinese statistics, [5]. Therefore, to classify and diagnose ENKTCL, ENKTCL constitutes 6.4% of non-Hodgkin lym- it is necessary to detect expression of CD2, phoma, and more than 20% of mature T- and CD56, cytoplasmic CD3 epsilon and cytotoxic NK-cell lymphoma [2]. The cause of the region- molecules such as granzyme B and TIA1 as well al difference in prevalence is related to environ- as EBV-encoded RNA (EBER) positivity [6]. mental and genetic factors, as recent studies based on the SEER registry show that the rate ENKTCL is usually classified according to the of ENKTCL is much higher in Asian/Pacific origin of the lesion into upper aerodigestive Islanders and Hispanics than in other popula- tract (UAT) and the non-upper aerodigestive tions [3]. ENKTCL is predominant in young and tract (non-UAT) type, and the prognosis and Immunotherapy targets for NK/T cell lymphoma

EBV-induced proliferation, such as overexpression of signalling pathway-related genes and mutation of single genes, have suggested new immunotherapy prospects for patients with L-asparaginase-refractory disease. In this review, we present the available literature and case reports and summarize the latest immunotherapy targets for ENKTCL (Figure 1).

Targeting tumour cell surface antigens or receptors

Anti-CD30 antibody-based therapy

CD30 is a transmembrane protein belonging to the tumour necrosis factor receptor family (Figure 2) that is reported to be specifically expressed in normal activated (rather than Figure 1. Summary of immunotherapy targets for static) B and T cells and NK cells, but not in NK/T cell lymphoma. normal cells. In terms of malignant lymphomas, CD30 is expressed in Hodgkin and Reed- treatment response of the latter are significant- Sternberg cells of Hodgkin’s lymphoma and in ly worse than those of the former [7]. Non-ad- almost all neoplastic cells of ALCL. Different vanced-stage disease occurs in approximately studies have reported a CD30 expression rate 70-80% of nasal/paranasal ENKTCL patients, in ENKTCL of approximately 50-70% [13]. and approximately half of them present with Furthermore, CD30 is more frequently ex- isolated nasal disease. In contrast, advanced pressed in ENKTCL than in other mature T cells disease occurs in 60% of extranasal cases [5]. and NK cell lymphoma subtypes, which is most Chemotherapy, such as CHOP and adriamycin- likely explained by the presence of EBV in based regimens, is largely ineffective due to ENKTCL patients [2]. the high expression levels of P-glycoprotein in NK lymphoma cells. However, lack of aspara- Overall, expression of CD30 varies in ENKTCL is gine synthase renders ENKTCL sensitive to variable and there is no consensus on its clini- L-asparaginase [8]. and L-asparaginase-con- cal significance [14]. One study including 70 taining chemotherapy regimens have led to a patients by Guan-Nan Wang and colleagues dramatic improvement in survival, particularly showed that compared with CD30-negative in relapsed/refractory ENKTCL [9]. Moreover, ENKTCL, patients with CD30-positive ENKTCL L-asparaginase-based regimens such as SMI- showed significantly worse OS (P = 0.023) and LE, AspaMetDex and P-Gemox are recommend- PFS (P = 0.008) [15]. In addition, strong CD30 ed by NCCN guidelines. In general, all of these expression was observed in atypical macronu- therapies have markedly improved the progno- clear cells in ENKTCL patients with primary sis of ENKTCL. For example, the 5-year and the skin, prostate and adrenal gland tumours, with 2-year overall survival (OS) of patients with poor outcomes, which may suggest that advanced disease were much higher after ENKTCL with large cells expresses CD30 and 2010 than before [10]. Nonetheless, approxi- predicts a poor prognosis [16]. In another study, mately 50% of patients with first-line treatment CD30-positive ENKTCL responded better to failure have poor clinical outcomes, with a non-anthracycline therapy than CD30-negative median progression free survival (PFS) of less ENKTCL among 72 cases, and the former than 8 months [11]. In addition, some patients patients with a COV (critical value) of 25% relapse after treatment with an L-asparaginase- showed a lower recurrence rate [17]. However, based regimen [12]. Thus the best treatment no correlation between CD30 expression and scheme should be further explored. The inher- survival outcomes was found in a study of 317 ent expression of targeted CD (cluster of differ- patients with ENKTCL and 91 patients with cat- entiation) markers and the intrinsic signs of alogued CD30 immunohistochemistry tissues

7035 Am J Transl Res 2020;12(11):7034-7047 Immunotherapy targets for NK/T cell lymphoma

by different researchers, and studies involving different co- horts have produced conflict- ing results [18]. Neverthele- ss, anti-CD30 antibodies are used in therapeutic strategies in many clinical trials, which provide a theoretical and prac- tical basis for the treatment of lymphoma.

A CD30-targeted antibody, brentuximab vedotin (BV) binds with monomethyl auristatin E (MMAE) to exert strong therapeutic effects in recurrent HL and multiple T-cell lymphoma through direct cytotoxicity, bystander effects, [19] and immune augmentation effects [20]. The results of a preliminary phase 2 study showed that SGN-30, a chimeric anti- CD30 monoclonal antibody, had modest efficacy in HL and ALCL [21]. However, responses to BV were observed in patients with all levels of CD30 expression in tumour samples, including 2 T cell lymphoma patients whose CD- 30 expression could not be detected by IHC in the central evaluation; this suggests that the drug may be dispersed into the tumour microenvironment and subsequently come into contact with tumour cells via the bystander effect [22]. Similar phenomena were also found for diffuse large B cell lymphoma [23]. In addition to the above mechanism of ac- tion, mouse models have sho- Figure 2. Summary of immunotherapy drugs or treatment strategies for NK/T cell lymphoma and their respective targets. Strategies targeting tu- wn increased activation of T mour cell surface antigens or receptors include brentuximab vedotin (CD30) cells, activation of dendritic and daratumumab (CD38). Strategies targeting intracellular signalling cells and migration to draining pathways and the microenvironment include anti-pd1 antibodies (such as lymph nodes after BV treat- pembrolizumab and nivolumab), targeted NF-κB drugs (bortezomib), JAK3 ment [24]. In general, some inhibitors (PRN371 and tofacitinib) and autologous T cells targeting LMP2 or results have been achieved LMP1 and LMP2 antigens. These strategies bring hope for this fatal disease. with BV similar to the latest phase 3 trial showing that, for (47.3%) [2]. These differences may be attribut- patients with CD30-positive peripheral T cell ed to the different cutoff values of CD30 used lymphomas, first-line treatment with A CHP

7036 Am J Transl Res 2020;12(11):7034-7047 Immunotherapy targets for NK/T cell lymphoma

(brentuximab vedotin, cyclophosphamide, dox- haematopoietic system, mainly by NK cells, orubicin, and prednisone) was better than that early precursor T cells, activated T cells and with CHOP (cyclophosphamide, doxorubicin, mature B cells, but the expression level in nor- vincristine, and prednisone) as it was associat- mal lymphocytes and myeloid cells is low [29]. ed with significantly improved PFS and OS [25]. CD38 interacts with the ligands CD31 and Regardless, tumour recurrence and drug resist- CD31/CD38, promotes the activation and pro- ance, major concerns, occur. Chen and col- liferation of different lymphocyte groups and is leagues reported that the percentage of CD30- expressed in almost all NKTLs. Wang L and col- positive cells in HL patients did not appear to leagues proved that 95% of ENKTCL cases be related to the degree of BV resistance, which were CD38 positive, with half of them highly may have been due to drug internalization expresseing CD38 [30]. Compared with ENK- changing the accumulation of MMAE in cells TCL patients with weak expression of CD38, and increasing expression of MDR1 (a known ENKTCL patients with strong expression had drug exporter) [26]. significantly poorer outcomes, suggesting the potential role of CD38 as a therapeutic target To date, no clinical trials have been conducted [31]. specifically for recurrent/refractory ENKTCL, but CR after BV treatment has been reported To date, several monoclonal antibodies against for two patients. In one case, a 63-year-old human CD38 have been successfully devel- male with CD30-positive non-UADT ENKTCL oped, such as daratumumab, isatuximab presented with multiple skin lesions. After four (SAR650984) and MOR202. Daratumumab is a cycles of single-dose brentuximab vedotin high-affinity therapeutic human mAb that rec- treatment, all skin lesions were cleared to com- ognizes the unique CD38 epitope. Its comple- plete remission (CR), though therapy was dis- ment-dependent cytotoxicity (CDC) and anti- continued because of secondary toxic dysp- body-dependent cytotoxicity are not affected noea, and the disease recurred three months by the presence of bone marrow stromal cells later [27]. In the other case, a 17-year-old [31]. Daratumumab has been approved in mul- woman with ENKTCL with CD30 expression in tiple combinations for pretreated and relapsed/ approximately 30% of neoplastic cells was refractory multiple myeloma (MM), which has treated with a combination regimen of brentuxi- greatly improved the survival outcomes of mab vedotin and bendamustine, and complete these patients [14]. However, the complete radiological remission (CR) was achieved after mechanism of daratumumab is still unclear two cycles of treatment; moreover, metabolic because even cases with high expression of CR was obtained on PET/CT after three courses CD38 may be primary refractory, and thus of treatment. Haploidentical haematopoietic expression of CD38 in MM does not correlate stem cells from her father were used for trans- significantly with response to daratumumab. plantation once remission was achieved and [32] Nonetheless, reducing the endocytosis of after transplantation, plasma EBV-DNA could complexed CD38/daratumumab can enhance not be detected [28] (Table 2). Unfortunately, the efficacy of the anti-tumour mAb [33]. For patients who receive bentuximab will eventual- those who are resistant to daratumumab, all- ly relapse, and the specific mechanism remains trans retinoic acid may increase CD38 expres- unclear. Currently, some clinical trials are using sion and decrease that of CD55 and CD59 on the combination of BV with L-asparaginase and MM cells, which can restore the CDC mediated non-L-asparaginase as the first-line regimen, by daratumumab [34]. These trials have been including one study that has completed accrual registered as NCT00574288 (GEN501) and (NCT01309789) and others that are still being NCT01985126 (SIRIUS). In leukaemia, daratu- planned (NCT0324750); their results are eager- mumab kills CLL cells through antibody-de- ly awaited. [14] Other ongoing studies are listed pendent cell-mediated cytotoxicity and anti- in Table 2. (NCT03192202 and NCT04074746) (Table 3). body-dependent cell phagocytosis, significantly prolonging the OS rate of CLL animal models Anti-CD38 antibody-based therapy [35]. Daratumumab has also been reported to be effective in the treatment of a 14-year-old CD38 is a type II glycosylated protein that acts child with CD38+Ph-positive recurrent B-ALL as a receptor, and is widely expressed in the [36].

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Table 1. Summary of available therapies for NK/T cell lymphoma using targeting markers or viral antigens Percentage of ENKTCLs Research stage in Target Prognostic relevance Targeted agent with positive expression ENKTCL CD30 50-70% [11] disputed brentuximab vedotin clinical CD30 CAR-T cells clinical CD38 95% [29] negative daratumumab clinical PD-1 NA NA pembrolizumab clinical nivolumab clinical NF-κB NA NA bortezomib clinical JAK3 NA NA tofacitinib clinical PRN371 preclinical EBV antigens NA NA LMP-CTLs clinical

The efficacy of daratumumab was reported and myeloid cells, and is structurally similar to among 2 patients with relapsed/refractory cytotoxic lymphocyte antigen-4 (CTLA-4). Bin- ENKTCL has been reported [37, 38]. In the first ding of ligands PD-L1 and PD-L2 by PD-1 leads case, a 56-year-old female patient with stage IV to T-lymphocyte dysfunction and T-cell-me- NK/T cell lymphoma exhibited EBV DNA positiv- diated cytotoxicity escape. Programmed death ity. The patient relapsed after 6 weeks of radio- ligand 1 (PD-L1) is a surface glycoprotein of therapy, cisplatin therapy and consolidated immune regulatory cells (Figure 2) that is main- chemotherapy. Subsequently, she received ly expressed at low levels on antigen-present- combined chemotherapy, intrathecal chemo- ing cells (APCs), including professional APCs therapy and allogeneic haematopoietic cell and non-professional APCs. PD-L1 is upregu- transplantation. Three weeks later, the disease lated in ENKTCL, ranging from 39 to 100%, recurred in the central nervous system, with which allows cells to avoid systemic surveil- systemic recurrence on day 90. However, after lance [39]. Almost all EBV-related lymphomas six weeks of daratumumab treatment, EBV are associated with high expression of PD-L1 became undetectable, and the patient reached [4]. However, studies have shown that NKTCL the longest sustained remission period (21 lymph node variants may have higher PD-L1 weeks) since her diagnosis. Daratumumab may expression than extranodal variants, which is also help patients who have undergone exten- not related to EBV expression [40]. Based on sive pre-treatment [37] (Table 2). Although clinical data, patients with elevated PD-L1 much research has been conducted on the expression had lower serum LDH levels and IPI drug in MM, its unique mechanism in NKTCL scores than patients with decreased PD-L1 lev- remains to be explored. Currently, several Asian els [41]. Several studies have also shown that countries are conducting phase 2 trials to serum PD-L1 levels are associated with the assess the safety and effectiveness of daratu- prognosis of ENKTCL [42]. For instance, Nagato mumab in ENKTCL (NCT02927925). At the and colleagues reported that elevated levels of 2018 American Society of Hematology (ASH) PD-L1 in tumour cells are associated with ele- meeting, preliminary results were reported that vated levels of PD-L1 in serum and worsened daratumumab had a good response rate in the OS [43], though the exact relationship remains treatment of relapsed and refractory ENKTCL patients (ORR: 35.7%), and the second stage of to be elucidated. Overall, the combination of the study is in progress (Table 3). high PD-L1 expression and foreign antigen expression in cancer cells makes the use of Targeting intracellular signalling pathways checkpoint inhibitors very attractive [44, 45]. and the microenvironment Anti-PD-1 antibodies such as pembrolizumab Programmed death 1 inhibitors and nivolumab can destroy the interaction between PD-L1 and PD-1, thereby restoring the As a member of the CD28 costimulatory recep- anti-tumour activity of activated T cells [46]. In tor superfamily, PD-1 is an immunosuppressive 2014, the U.S. FDA approved pembrolizumab receptor expressed by activated T cells, B cells and nivolumab for the treatment of metastatic

7038 Am J Transl Res 2020;12(11):7034-7047 Immunotherapy targets for NK/T cell lymphoma

Table 2. Select reports of targeted therapy for extranodal NK/T cell lymphoma Target/therapy Patients characteristics Efficacy Reference CD30 Brentuximab vedotin Refractory or relapsed HL or CD30(+) NHL patients Modest efficacy. [21] A male with ENKTCL and CD30 expression CR was achieved after four cycles of treatment. [27] Brentuximab vedotin and bendamustine A woman with ENKTCL and CD30 expression After two cycles of treatment, CR was achieved. [28] Brentuximab vedotin, cyclophosphamide, doxorubicin, and Patients with CD30-positive peripheral T cell lymphomas Significant improvement in progression-free [28] prednisone (A+CHP) survival and overall survival. BV with L-asparaginase and non-L-asparaginase 26 patients with CD30+ PTCL All patients (n = 26) achieved an objective [14] response (CR rate, 88%; estimated 1-year PFS rate, 71%). CD38 Daratumumab A child with CD38+ recurrent B-ALL Effective. [36] A patient with stage IV NKTCL Patients reached a maximum sustained remis- [37] sion period of 21 weeks. PD-1 Nivolumab 29 patients with recurrent or refractory lymphatic malignancies A DBLCL patient and one with FL reached CR. [48] 3 patients with relapsed/refractory NKTCL All patients achieved a clinical response. [44] Pembrolizumab 7 patients with NKTCL All patients achieved CRs. [50] 7 patients with NKTCL 2 patients reached CR and 2 reached PR. [45] 30 consecutive patients with relapsed/or refractory NHL 7 patients reached CR and 7reached PR. [51] NF-κB B-GIFOX (bortezomib, gemcitabine, oxaliplatin and ifosfamide) 6 ENKTCL patients The ORR was 42.8%. - Bortezomib, fludarabine and autologous haematopoietic stem A patient with relapsed/refractory NKTCL The patient remained disease-free as of March [59] cell transplantation 2017. EBV antigens Activated/stimulated T cells and LMP1/2- or LMP2-targeted 52 patients with EBV-related lymphoma 11 patients with active disease reached CR, 2 [63] strategies patients achieved PR, and 5 ENKTCL patients reached CR. 8 patients with localized disease and 2 advanced ENKTCL All patients reached CR: OS and PFS were [65] patients 100% and 90%, respectively. CAR-T CD19-CAR-T cells 119 patients with B cell malignancies Response rates (93%) were higher in all [66] patients than in CLL patients (62%) and lymphoma patients (36%). CD22-CAR-T cells 34 patients with B-ALL 24 patients achieved CR or CRI. [70] CD28 co-stimulated anti-CD30 CAR-T cells 7 patients with relapsed/refractory HL and 2 patients with 2 patients with HL reached CR and 3 reached [67] ALCL SD; 1 ALCL patients reached CR. 4-1BB co-stimulated anti-CD30 CAR-T cells 17 HL patients and 1 cutaneous ALCL patients 7 patients achieved PR and 6 patients [68] achieved SD. EBV, Epstein-Barr virus; CR, complete response; PR, partial response; SD, stable disease; HL, Hodgkin’s lymphoma; ALCL, anaplastic large cell lymphoma; ENKTCL, extranodal NK/T cell lymphoma; PTCL, peripheral T cell lymphoma; OS, overall survival; PFS, progression-free survival; B-ALL, B cell acute lymphoblastic leukaemia.

7039 Am J Transl Res 2020;12(11):7034-7047 Immunotherapy targets for NK/T cell lymphoma

Table 3. Clinical trials of targeted therapy for various lymphomas, particularly for NK/T cell lymphoma Intervention/treatment Phase Tumour type ClinicalTrials.gov Identifier CD30 AFM 13 Phase 1 Relapsed/Refractory cutaneous lymphomas NCT 03192202 Phase 2 Modified immune cells (AFM13-NK) Phase 1 Recurrent or refractory CD30-positive HL or NHL NCT 04074746 CD38 Daratumumab Phase 2 Relapsed or refractory NKTCL NCT 02927925 PD-1 Pegaspargase and anti-PD-1 monoclonal antibody Phase 2 ENKTCL, nasal type NCT 04096690 PD-1 antibody, chidamide, lenalidomide and etoposide Phase 4 NKTCL NCT 04038411 SHR1210 Phase 2 NKTCL NCT 03701022 Phase 2 ENKTCL, nasal type NCT 03363555 LEAP regimen Phase 2 ENKTCL, nasal and nasal-type NCT 04004572 Pembrolizumab Phase 2 T cell Lymphoma NCT 03021057 NK cell lymphoma Phase 2 NKTCL of the nasal cavity NCT 03728972 NKTCL of the nasopharynx Phase 1 and phase 2 ENKTCL and EBV-related DLBCL NCT 03586024 MK-3475 and copanlisib Phase 1 and phase 2 NK and T cell non-Hodgkin’s lymphoma NCT 02535247 Pembrolizumab and pralatrexate Phase 1 and phase 2 T cell lymphomas NCT 03598998 Nivolumab Phase 2 PTCL NCT 03075553 Phase 2 T cell and NK cell lymphomas, cutaneous squamous cell carcinoma, Merkel cell NCT 02978625 carcinoma, and other rare skin tumours JAK3 Tofacitinib and chidamide Phase 2 ENKTCL NCT 03598959 CAR-T CD7 CAR-T cells infusion Phase 1 T-lymphoblastic lymphoma and NCT 04004637 NKTCL Anti-CD30 CAR-T cells Phase 1 Relapsed/refractory lymphocyte malignancies NCT 04008394 Phase 1 HL, ALCL, PTCL NOS, DLBCL NOS, PMBCL, grey zone lymphoma, enteropathy-associ- NCT 03049449 ated T cell lymphoma or ENKTCL Phase 1 and phase 2 Relapsed and refractory CD30-positive lymphomas NCT 02274584 CD7-specific CAR gene-engineered T cells Phase 1 and phase 2 T-ALL, TCL, NKTCL and AML NCT 04033302 CD19-TriCAR-T/SILK Early phase 1 CD19+ children with leukaemia or non-Hodgkin’s lymphoma NCT 03910842 PD-1, programmed death 1; LMP, latent membrane protein; EBV, Epstein-Barr virus; CR, complete response; PR, partial response; SD, stable disease; CAR-T cell, chimeric antigen receptor T cell; HL, Hodgkin’s lymphoma; ALCL, anaplastic large cell lymphoma; ENKTCL, extranodal NK/T cell lymphoma; PTCL NOS, peripheral T cell lymphoma not otherwise specified; DLBCL NOS, diffuse large B cell lymphoma not otherwise specified; PMBCL, primary mediastinal B cell lymphoma; T-ALL, T cell acute lymphoblastic leukaemia; TCL, T cell lymphoma; AML, acute myeloid leukaemia.

7040 Am J Transl Res 2020;12(11):7034-7047 Immunotherapy targets for NK/T cell lymphoma melanoma, and in 2015, nivolumab was tation. A number of clinical trials are currently approved for the treatment of squamous NS- underway to evaluate the efficacy of anti-PD1 CLC. Over time, both drugs have been approved therapy for ENKTCL (NCT04096690, NCT- for use in many types of cancer, leading to 04038411, NCT03701022, NCT03363555, unprecedented clinical advances. At present, NCT04004572, NCT03021057, NCT037289- preliminary results published by some institu- 72, NCT03586024, NCT02535247, NCT035- tions support the use of PD-1/PD-L1 signalling 98998, NCT03075553, and NCT02978625) pathway inhibitors in a variety of tumours (e.g., (Table 3). digestive tract tumours, liver cancer, triple-negative breast cancer, advanced urothelial can- NF-κB inhibitors cer, ovarian cancer, advanced Hodgkin’s lymphoma) [47]. Indeed, many large-scale studies NF-κB (nuclear factor κappa-light-chain-en- of PD-1/PD-L1 monoclonal antibodies are in hancer of activated B cells) is a transcription clinical stages I and II. Among these monoclo- factor that mediate the development, prolifera- nal antibodies, nivolumab has been tested in tion and survival of T cells and B cells; changes many clinical trials with good results. In one in NF-κB activity will cause constitutive activa- study, 29 patients with recurrent or refractory tion of lymphocyte proliferation and/or block- lymphatic malignancies were evaluated, includ- age of cell death, which can promote the occur- ing one DLBCL patient (9%) and one FL patient rence and development of tumours [52]. Two (10%) who reached CR [48]; the remaining 27 GEP (gene expression profiling) studies have patients showed some response or tumour found significant enrichment of genes in the shrinkage after treatment. In another inde- NF-κB pathway in cancer [53]. It has been prov- pendent study, low-dose nivolumab was used en that there is pathogenic cooperation bet- in 3 patients with relapsed and refractory ween p53 deletion and NF-κB activity and that ENKTCL, which achieved a clinical response activation of NF-κB is related to poor survival in [49]. Pembrolizumab is another completely ABC DLBCL [54]. In one study, p52 (NF-κB subu- humanized PD-1 monoclonal antibody, and nit) nuclear staining was observed in 65.2% of Kwong and colleagues have confirmed the effi- ENKTCL cases as an alternative indicator to cacy of pembrolizumab in patients with ENKTCL determine activation of NF-κB and correlate its [50]. Among seven relapsed and refractory status with survival. Moreover, the 2-year PFS patients with advanced disease who had previ- and OS rates of 8 p52-positive patients were ously been treated with SMILE or SMILE plus lower than those of 8 p52-negative patients platinum regimens, all displayed a rapid [55]. Therefore, the NF-κB signalling pathway is response after 7 cycles of pembrolizumab and an attractive therapeutic target in T- and B-cell 5 achieved CR. Pembrolizumab was effective in malignancies. 4 of 7 NKTCL patients (2 with complete remission and 2 with partial remission, with a total Bortezomib, a dipeptidyl boric acid, is associat- response rate of 57%) in another study [45]. ed with tumourigenesis, cell cycle progression, Seok-Jin Kim and colleagues found that seven apoptosis and multiple drug resistance, which EBV-positive NHL patients, including NK/T cell can lead to stabilization of the inhibitory protein lymphoma patients (6/14, 44%) and one pri- IκBα and decrease the activity of NF-κB [56]. mary mediastinal B cell lymphoma patient Bortezomib has achieved remarkable results in (1/4, 25%), responded to pembrolizumab, with the treatment of relapsed and refractory multi- patients with EBV-negative subtypes, such as ple myeloma [57]. And bortezomib can also diffuse large B cell lymphoma and PD-L1 play an anti-tumour role in leukaemia. In both expression showing higher responses (4/6, laboratory and clinical studies, bortezomib has 67%) than those with low PD-L1 expression shown some progress in the treatment of (1/5, 20%) [51] (Table 2). This phenomenon chronic myeloid leukaemia, chronic lymphocyt- also has some significance and according to ic leukaemia, acute myeloid leukaemia, acute some studies, combination with other immuno- lymphocytic leukaemia, adult T-lymphocytic therapies such as anti-CD38 antibodies or BV, leukaemia and plasma cell leukaemia. Bor- can enhance efficacy [4]. Overall, there has tezomib-based combinations targeting NF-κB been a good response to PD-L1 inhibitors, have also been evaluated for ENKTCL, though though the short reaction time is the main limi- data are available for only small groups of

7041 Am J Transl Res 2020;12(11):7034-7047 Immunotherapy targets for NK/T cell lymphoma patients. In a study involving six ENKTCL pa- as well as fewer side effects than other JAK3 tients, the ORR due to B-GIFOX (bortezomib (B), inhibitors. M.-L. Nairismägi and colleagues pre- gemcitabine (G), oxaliplatin (OX) and ifosfamide clinically evaluated PRN371 for the first time (IF)) regimens was 42.8% in newly diagnosed and found that it significantly inhibited tumour patients, but the median PFS was relatively growth in an NKTCL xenotransplantation model short at approximately 4 months [58] (Table 2). carrying JAK3 activating mutations, which is B-GIFOX is a promising regimen for ENKTCL, consistent with in vitro results [61]. The JAK3 and a prospective phase 2 study is currently inhibitory antineoplastic activity seen in pre- being designed to verify its efficacy in treating clinical/in vitro models demonstrates the bio- ENKTCL. In addition, bortezomib inhibits the logical basis for targeting these pathways. repair of DNA damage induced by fludarabine, Although the frequency of JAK3 mutations is and this synergistic effect enhances the anti- controversial, PRN371 is effective in most tumour effect accordingly, bortezomib-fludara- ENKTCL cells, including most cases with STAT3 bine chemotherapy may be an effective reme- mutations, and can act on other downstream dial strategy for recurrent ENKTCL. In one case, pathways of JAK3, such as the EZH2 pathway. a 40-year-old patient who relapsed after hor- Therefore, a subset of patients stratified based mone therapy combined with radiotherapy and on appropriate molecular markers can use chemotherapy was treated with two courses of PRN371 as an alternative to current chemo- remedial therapy containing bortezomib and therapies, a strategy that can be translated fludarabine and received autologous haemat- into clinical trials to clarify clinical impact and opoietic stem cell transplantation; the patient effectiveness [61]. In addition, the JAK1/2 remained disease-free as of the last follow-up inhibitor ruxolitinib has been approved for treat- (March 2017) [59] (Table 2). Nevertheless, larg- ment of bone marrow fibrosis. Phase 2 clinical er trials are needed to provide a more compre- trials evaluating JAK inhibitors in ENKTCL are hensive assessment of the efficacy and safety being conducted in patients with recurrent of bortezomib, and early clinical trials of ENK- ENKTCL (NCT02974647 and NCT03598959) TCL are underway. [62].

JAK3 inhibitors LMP-CTLs

Janus kinase (JAK) family members include Tumour cells from approximately 40% of JAK1, JAK2, JAK3 and TYK2, which play roles in patients with Hodgkin’s or non-Hodgkin’s lym- different signalling pathways mediated by cy- phoma express type II Epstein-Barr virus (EBV) tokines and growth factor receptors (Figure 2). latent membrane protein 1 (LMP1) and LMP2, JAK3, a non-receptor tyrosine kinase involved inducing attack by LMP-cytotoxic T lympho- in the JAK-STAT pathway, is mainly expressed cytes (CTLs). Therefore, expanding LMP-CTLs in in haematopoietic cells and helps to regulate ENKTCL to target EBV antigens can achieve the development of lymphocytes [60]. In one anti-tumor effects [63]. In fact, this strategy report, 5 of 71 ENKTCL patients (7.0%) har- has shown therapeutic efficacy in a variety of boured novel JAK3 mutations (JAK3 H583Y and EBV-derived lymphomas and can result in a JAK3 G589D), which inhibited the proliferation lasting complete response without significant of Ba/F3 cells and were carcinogenic in NKTCL toxicity but with high specificity [63]. Using this [60]. Pathway inhibition might be a therapeutic robust and cost-effective approach in the treat- option for NKTCL patients with JAK3 mu- ment of EBV-related lymphoproliferative dis- tations. eases after transplantation also leads to con- tinuous complete remission (CRs in 68-84% of Tofacitinib can significantly inhibit JAK3 activity patients) [64]. Bollard and colleagues treated in vivo and in vitro, but its clinical application in 52 patients with EBV-related lymphoma, using cancer treatment is limited by pan-JAK inhibi- LMP1/2-or LMP2-targeted and stimulated tory activity. PRN371 is a small molecule that CTLs [63]. LMP2- or LMP1/2-specific CTLs were was designed as an effective and selective administered to 50 EBV-related HL or NHL JAK3 inhibitor, that specifically binds to cysteine patients, which proved to be safe. The 2-year 909 of JAK3 kinas. PRN371 has high selectivity EFS rate was 82% in 29 patients with high-risk and durability and stronger anti-tumour activity or recurrent disease in the remission stage.

7042 Am J Transl Res 2020;12(11):7034-7047 Immunotherapy targets for NK/T cell lymphoma

Among the 21 patients with active disease, 11 enced disease progression during brentuximab received CTL treatment and entered into con- treatment. However, two patients with HL who tinuous CR, and the other 2 achieved PR. Five reached complete remission (CR) sustained it of the 11 ENKTCL patients received CTLs as for more than 2 years, and 3 patients had tran- consolidation therapy after initial radiotherapy sient stable disease. One ALCL patient achieved or autologous stem cell transplantation and CR for more than 9 months, and no patient remained in CR for 2-6 years. A patient with a developed impaired virus-specific immunity. primary refractory disease who acquired CR Additionally, Wang CM et al. treated 17 HL after autologous stem cell transplantation and patients and 1 cutaneous ALCL patient with a retained it for 2 years after CTL infusion may 4-1BB co-stimulated anti-CD30 CAR-T cell con- prove the effectiveness of this approach. struct, with seven achieving PR and six stable disease (Table 1). Hence, an increasing num- Although these results may be significant for ber of studies have applied CAR-T cell therapy high-risk relapsed/refractory patients, they do for breast cancer, sarcoma, neuroblastoma not demonstrate the role of CTLs as a mainte- and other solid tumours and explored its clini- nance therapy for local disease after first-line cal value [68]. Compared with haematological treatment. Cho and colleagues studied LMP1/ malignancies, the application of CAR-T cells for 2-directed CTL treatment in eight patients with solid tumours is limited by many factors, includ- localized disease and two advanced ENKTCL ing inhibited T cell functions and T cell localiza- patients, and all patients reached CR in 4 tion [69]. Therefore, the application of CAR-T years, with OS and PFS values of 100% and cell immunotherapy in solid tumours remains at 90%, respectively. [65] Only one patient had an the safety-determining stage. Overall, CAR-T initial recurrence of IVE disease after 32 cell therapy is feasible for the treatment of months, which suggests that CTLs can induce NKTCL and even the relapsed or refractory persistent complete remission without signifi- NKTCL. Several clinical trials with anti-CD7 cant toxicity. However, as the 5-year survival CAR-T cells and similar molecules are ongo- rate of chemical radiation can be as high as ing (NCT04004637, NCT04008394, NCT030- 90%, it remains unclear whether patients with 49449, NCT02274584, NCT04033302, and early disease truly benefit from maintaining CTL NCT03910842) (Table 3). infusion (Table 2). In conclusion, T cell immuno- Conclusion therapy with immunity stimulated by Epstein- Barr virus (EBV) may play an important role in Overall, there has been great progress in our the targeted treatment of EBV-related cancer. understanding and treatment of NK/T cell lymphoma in recent years. As immunotherapy has Intracellular immunotherapy in humans broader anticancer effects and fewer side CAR-T (chimeric antigen receptor T) cells are a effects than existing individual therapies and type of antigen-specific T cell ithw extracellular combination therapies, it may provide more effective treatment options. There are specific single-chain variant fragments that recognize drugs for CD30, CD38, PD-1, NF-κB, JAK1/2/3 antigens coupled to activated intracellular inhibitors, but EBV antigen and CAR-T cell treat- domains and then bind to them. Thus far CAR-T ment strategies need to be further researched. cell immunotherapy has achieved remarkable Nevertheless, few patients have improved out- therapeutic effects in the treatment of haema- comes, and there are almost no phase 3 clini- tological malignancies, for example, the treat- cal trials to guide treatment in this area. In ment of B cell malignancies with allogeneic brief, the effect of existing therapeutic meth- CD19-CAR-T cells [66] (Table 2). Targeting ods is still unsatisfactory, especially for CD30 with CD30 CAR T cells provides an oppor- relapsed/refractory ENKTCL. A large number of tunity for the rapid production of tumour-specif- new immunotherapy clinical trials need to be ic T cells in various lymphoma patients, reduc- carried out. ing side effects and enhancing anti-tumour activity, regardless of EBV status. In a phase 1 Acknowledgements dose-escalation study, CD28 co-stimulated anti-CD30 CAR-T cells were used to treat 7 This study was supported by grants from the patients with relapsed/refractory HL and 2 National Natural Science Foundation of China patients with ALCL [67]. Seven patients experi- (No. 8187010857).

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