Fig 3 - available via license: CC BY
Content may be subject to copyright.
PET/CT results of case 2. The scan of case 2 in the left two images showed a relatively hypermetabolic lesion in mediastinal, hilar lymph nodes, and intestines after using pembrolizumab for 1 cycle. The two images on the right showed that the lesions were metabolically less active 2 cycles later
Source publication
Natural killer/T-cell lymphoma (NKTCL) is a rare subtype of non-Hodgkin lymphoma that is associated with a poor outcome. Currently, the treatment needs of NKTCL remain unmet, and efforts to further improve treatment are urgently needed. Herein, seven patients with NKTCL who failed to respond to various types of chemotherapies were treated with the...
Context in source publication
Similar publications
Extranodal natural killer (NK)/T cell lymphoma (ENKTL) is a distinct subtype of Non-Hodgkin's lymphoma mainly involving the nasal area. Since the entity was first recognized, treatment strategies have been evolving from anthracycline-based chemotherapy and radiotherapy to L-asparaginase containing regimens and recently immune checkpoint inhibitors....
Citations
... The available data suggest that PD1/PDL1 monoclonal antibody monotherapy or combination therapy is a rational and efficacious treatment for both newly diagnosed and recurrent/ refractory ENKTL. The response rate was 38-75% for monotherapy in patients with relapsed/refractory NK/T-cell lymphoma [18][19][20][21] and 88.9% for PD-1 inhibitors in combination with P-GemOx chemotherapy in patients with advanced ENKTL [22]. However, a certain proportion of patients benefit less from immunotherapy, and an assessment of immunotherapy response biomarkers that can identify patients who will benefit from immunotherapy is urgently needed. ...
Immunotherapy with programmed cell death 1 ligand 1 (PD-L1) blockade was effective in patients with NK/T-cell lymphoma. In addition to PD-L1, indoleamine 2,3-dioxygenase-1 (IDO1) is one of the most promising immunotherapeutic targets. High proportions of PD-L1 and IDO1 proteins were observed by immunohistochemistry (IHC) from 230 newly diagnosed patients with NK/T lymphoma with tissue samples from three cancer centers and were associated with poor overall survival (OS) in patients with NK/T lymphoma. Importantly, the coexpression of PD-L1 and IDO1 was related to poor OS and short restricted mean survival time in patients with NK/T lymphoma and was an independent prognostic factor in the training cohorts, and which was also validated in 58 NK/T lymphoma patients (GSE90597). Moreover, a nomogram model constructed with PD-L1 and IDO1 expression together with age could provide concise and precise predictions of OS rates and median survival time. The high-risk group in the nomogram model had a positive correlation with CD4 + T-cell infiltration in the validation cohort, as did the immunosuppressive factor level. Therefore, high PD-L1 and IDO1 expression was associated with poor OS in patients with NK/T lymphoma. PD-L1 and IDO1 might be potential targets for future immune checkpoint blockade (ICB) therapy for NK/T lymphoma.
... Thus, more effective and tolerable salvage treatments with different mode of action from conventional chemotherapies. Gene profiling data of ENKTL has revealed increased activation of the JAK/STAT pathway in ENKTL cells, with increased STAT3 activation of PD-L1 (programmed cell death-ligand 1) and therefore increased PD-L1 expression [8][9][10]. Use of the immune checkpoint inhibitors (ICIs) pembrolizumab and nivolumab to inactivate PD-1 (programmed death protein 1) and avelumab to inactive PD-L1 in ENKTL is, therefore a viable treatment option for relapsed/refractory ENKTL (R/R ENKTL) [11]. ...
... Pembrolizumab is a salvage treatment option for R/R ENKTL. [10,22,23]. Although long-term use of pembrolizumab until disease progression has been approved in Korea, guidelines concerning optimal treatment duration and markers to determine interruption timing have still not been agreed upon. ...
Pembrolizumab (anti-programmed cell death-ligand 1 inhibitor) is a promising salvage therapeutic option for relapsed/refractory extranodal NK/T-cell lymphoma (R/R ENKTL). However, the appropriate duration of pembrolizumab use in R/R ENKTL patients and the optimal timing for administering pembrolizumab remain undetermined. We collected and analyzed clinical information on R/R ENKTL 58 patients who received pembrolizumab to evaluate the optimal treatment durations and clinical information for considering treatment interruption. Treatment outcomes were assessed by 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) and Epstein Barr virus DNA (EBV DNA) every 3 months. Nineteen (32.8%) patients had been treated with more than three chemotherapies before pembrolizumab administration. The best response rate towards the first try of pembrolizumab was 38.9% (31.5% complete response rate (CR), 7.4% partial response (PR)). During the 41.8-month median follow-up duration, the median progression-free survival (PFS) was 3.1 months, and the median overall survival (OS) was 7.1 months. The failure group, which was characterized by Deaville score (DS) 3–4 and circulating EBV detection, or DS 5 with/without EBV detection, had the worst PFS (p < 0.001) and OS (p < 0.001), followed by the high (DS 1–2 and EBV detection, or DS 3–4 and EBV not detected) and low-risk groups (DS 1–2 and EBV not detected). Among the 21 patients who achieved the best response at the first pembolizumab try, the patients who received planned 24 cycles presented better PFS than those who received incomplete cycles (57.6 months vs 20.9 months, P-value = 0.012). Among 13 patients who received avelumab or pembrolizumab in advance, a few who responded to the second trial of pembrolizumab administration had over one year of chemotherapy vacation. Determining the discontinuation or continuation of pembrolizumab would be considered in selected cases assessed by PET-CT and EBV monitoring. Disruption of pembrolizumab treatment may be advisable for the low-risk group(DS 1–2 and EBV not detected), whereas continuation could be warranted for the high-risk group (DS 1–2 and EBV detection, or DS 3–4 and EBV not detected). Moreover, it might be critical to maintain over 24 cycles to improve the survival outcome of R/R ENKTL.
... Ligation of PD1 with PDL1 inhibits T cell cytotoxicity (21,22) and the use of anti-PD1 perturbing this receptor/ligand interaction can unleash the suppressed cytotoxicity of T cells to kill the tumor cells (23). In patients with relapsed/refractory NKTL the efficacy of ICI therapy was demonstrated with anti-PD1 antibodies such as Pembrolizumab or Nivolumab, which reportedly achieved complete response (CR) in around 30-70% of the patients (24)(25)(26)(27)(28). ...
... In spite of the apparent effectiveness of ICI-based immunotherapies, they often work only in a subset of patients (24)(25)(26)(27). A common strategy to increase treatment efficiency is through the combination with other (immune-) therapies to synergize their effects (29). ...
... NKTL patients that failed L-asparaginase chemotherapy are usually faced with a dismal outcome (77). While ICI has shown to be a promising treatment for relapsing NKTL patients, the ORR ranges from 37-54% (11,24,25,27,61). As ICI and anti-CD38 therapy function through different mechanisms, the possibility of combining ICI and anti-CD38 to improve patient outcome was raised (30). ...
Introduction
Natural killer/T cell lymphoma (NKTL) is an aggressive malignancy associated with poor prognosis. This is largely due to limited treatment options, especially for relapsed patients. Immunotherapies like immune checkpoint inhibitors (ICI) and anti-CD38 therapies have shown promising but variable clinical efficacies. Combining these therapies has been suggested to enhance efficacy.
Methods
We conducted a case study on a relapsed NKTL patient treated sequentially with anti-CD38 followed by ICI (anti-PD1) using cytometry analyses.
Results and Discussion
Our analysis showed an expected depletion of peripheral CD38+ B cells following anti-CD38 treatment. Further analysis indicated that circulating anti-CD38 retained their function for up to 13 weeks post-administration. Anti-PD1 treatment triggered re-activation and upregulation of CD38 on the T cells. Consequently, these anti-PD1-activated T cells were depleted by residual circulating anti-CD38, rendering the ICI treatment ineffective. Finally, a meta-analysis confirmed this counterproductive effect, showing a reduced efficacy in patients undergoing combination therapy. In conclusion, our findings demonstrate that sequential anti-CD38 followed by anti-PD1 therapy leads to a counterproductive outcome in NKTL patients. This suggests that the treatment sequence is antithetic and warrants re-evaluation for optimizing cancer immunotherapy strategies.
... Several immune-checkpoint inhibitors have gained approval for treating solid tumors [3][4][5][6][7][8] . Furthermore, ICT has demonstrated therapeutic efficacy against hematologic malignancies (HMs) 9,10 . ...
Objective: The human cluster of differentiation (CD)300A, a type-I transmembrane protein with immunoreceptor tyrosine-based inhibitory motifs, was investigated as a potential immune checkpoint for human natural killer (NK) cells targeting hematologic malignancies (HMs). Methods: We implemented a stimulation system involving the CD300A ligand, phosphatidylserine (PS), exposed to the outer surface of malignant cells. Additionally, we utilized CD300A overexpression, a CD300A blocking system, and a xenotransplantation model to evaluate the impact of CD300A on NK cell efficacy against HMs in in vitro and in vivo settings. Furthermore, we explored the association between CD300A and HM progression in patients. Results: Our findings indicated that PS hampers the function of NK cells. Increased CD300A expression inhibited HM lysis by NK cells. CD300A overexpression shortened the survival of HM-xenografted mice by impairing transplanted NK cells. Blocking PS–CD300A signals with antibodies significantly amplified the expression of lysis function-related proteins and effector cytokines in NK cells, thereby augmenting the ability to lyse HMs. Clinically, heightened CD300A expression correlated with shorter survival and an “exhausted” phenotype of intratumoral NK cells in patients with HMs or solid tumors. Conclusions: These results propose CD300A as a potential target for invigorating NK cell-based treatments against HMs.
... Immunotherapies have become a promising treatment option in relapsed/refractory NKTCL [13][14][15][16][17]. Strong expression of PD-L1 was reported to be a predictor of favorable survivals for patients receiving traditional treatment or anti-PD1/PD-L1 blockades [16][17][18]. ...
... Previous studies have shown that absolute lymphocyte count (ALC) is an independent prognostic indicator for survivals in multiple NHLs [21][22][23][24][25]. A retrospective study reported that patients with newly-diagnosed NKTCL who had high ALC (> 1.0 × 10 9 /L) at diagnosis achieved superior 5-year OS (60.4% vs. 13.1%, P < 0.001) and complete remission rate (CRR, 52% vs. 28%, P = 0.001) in comparison to those with low ALC [26]. ...
This study aimed to explore the distribution, characteristics and prognostic value of baseline peripheral blood lymphocyte subsets in patients with extranodal NK/T-cell lymphoma (NKTCL). We conducted this cross-sectional study of 205 newly-diagnosed NKTCL patients receiving first-line chemotherapy and radiation at our institute between 2010 and 2020. Baseline peripheral blood lymphocytes were detected using flow cytometry, and the clinical value was analyzed. Compared with healthy controls, patients with NKTCL presented with a distinct peripheral immunity with higher levels of cytotoxic CD8+ T cells (33.230 ± 12.090% vs. 27.060 ± 4.010%, p < 0.001) and NKT cells (7.697 ± 7.219% vs. 3.550 ± 2.088%, p < 0.001) but lower proportions of suppressive regulatory T cells (Treg, 2.999 ± 1.949% vs. 3.420 ± 1.051%, p = 0.003) and CD4+ helper T cells (Th, 33.084 ± 11.361% vs. 37.650 ± 3.153%, p < 0.001). Peripheral lymphocytes were differentially distributed according to age, stage, and primary site in patients with NKTCL. The proportion of Th cells/lymphocytes was associated with tumor burden reflected by stage (p = 0.037), serum lactate dehydrogenase (p = 0.0420), primary tumor invasion (p = 0.025), and prognostic index for NK/T-cell lymphoma (PINK) score (p = 0.041). Furthermore, elevated proportions of T cells (58.9% vs. 76.4%, p = 0.005), Th cells (56.3% vs. 68.8%, p = 0.047), or Treg cells (49.5% vs. 68.9%, p = 0.040) were associated with inferior 5-year progression-free survivals (PFS) via univariable survival analysis. Multivariate cox regression revealed elevated Th cells as an independent predictor for unfavorable PFS (HR = 2.333, 95% CI, 1.030–5.288, p = 0.042) in NKTCL. These results suggested the proportion of Th cells positively correlated with tumor burden and was a potential non-invasive biomarker for inferior survival for patients with NKTCL.
... Extranodal NK/ T-cell lymphomas, which are typically associated with EBV and show increased PD-L1 expression, respond favorably to PD-1/PD-L1 inhibition. 35,36 Results for using PD-1/PD-L1 inhibitors in PTCL have been variable in early-phase trials with only modest activity. 37,38 Moreover, the concerning phenomenon of hyperprogression (rapid progression of disease after one round of treatment) in a subset of patients with PTCL has been noted in multiple studies. ...
Immune checkpoint inhibitors against Programmed Cell Death Protein 1/Programmed Cell (PD-1/PD-L1) and CTLA-4/B7 axes have had limited success in hematologic malignancies, requiring the need to explore alternative targets such as T-cell immunoreceptor with Ig and ITIM domains (TIGIT)/CD155 to improve durable clinical responses. We undertook this study to investigate the expression profile of TIGIT such that the potential efficacy of TIGIT blockade could be mapped among lymphoma subtypes. We validated an immunohistochemical assay for TIGIT and evaluated its expression in lymphoma and tumor microenvironment (TME) cells in 661 lymphoma/leukemia biopsies. Multiplex immunofluorescence was used for correlation with normal TME cell subsets. Tumor or TME TIGIT-positivity was defined as moderate to strong membrane staining in at least 10% of tumor or TME cells, respectively. TME TIGIT expression was correlated with overall survival and progression-free survival and comparison with PD-L1 expression. In most cases, lymphoma cells were TIGIT-negative except for angioimmunoblastic and peripheral T-cell lymphomas, which showed 91% and 47% positivity, respectively. A high proportion of small B-cell lymphoma and anaplastic large cell lymphoma cases had TIGIT-positive TME cells. Chronic lymphocytic leukemia/small lymphocytic lymphoma patients with TIGIT-negative TME cells showed significantly shorter overall survival ( P =0.04). No other statistically significant differences were found. When TIGIT was expressed in TME cells, there were a comparable number of TIGIT-positive only and dual TIGIT/PD-L1 positive cases except for more TIGIT-positive only cases in CLL/SLL. TIGIT expression shows distinctive profiles among lymphoma subtypes. Chronic lymphocytic leukemia/small lymphocytic lymphoma and anaplastic large cell lymphoma demonstrated high TME TIGIT expression compared with PD-L1, with a high proportion of dual TIGIT and PD-L1-positivity. Our results are likely to contribute to the design and correlative study of therapeutic response in clinical trials targeting TIGIT alone or in combination with PD1/PDL1.
... Anti-PD-1 immune checkpoint inhibitor has demonstrated preliminary efficacy and a favorable safety profile in relapsed/refractory and advanced-stage ENKTCL; the overall response rate of mono-immunotherapy was around 30% (among series with studied number >10, the complete response [CR] rate ranged from 7 to 37%) [16][17][18][19][20][21][22][23][24][25]. ...
... Considering the prevalent EBV-induced pathogenesis of ENKTCL and LMP1-directed overexpression of PD-L1, anti-PD-1 antibodies remain an attractive immunotherapy option for this disease. The concept of restoring and sustaining antitumor immunity via inhibition of immune checkpoints such as PD-1/PD-L1 provided a new prospect for the treatment of ENKTCL, as several studies have demonstrated encouraging response rates and durable efficacy [16][17][18][19][20][21][22][23][24][25]. ...
Low-risk early-stage extranodal natural killer/T-cell lymphoma, nasal type has a favorable outcome with radiation therapy alone, and the addition of chemotherapy shows no survival benefit. Nonetheless, a proportion of patients will relapse or progress, with a dismal outcome, highlighting the need for a novel therapeutic strategy. Promising preliminary findings indicate the efficacy of PD-1/PD-L1 inhibitors in extranodal natural killer/T-cell lymphoma, nasal type, with good toxicity profiles. Here we describe the design of a phase II study (CLCG-NKT-2101), which is evaluating the safety and efficacy of adding anti-PD-1 antibody to the current radiation therapy regimen in low-risk early-stage extranodal natural killer/T-cell lymphoma, nasal type patients. Tislelizumab will be added in an inductive and concurrent way to radiation therapy. The primary end point will be the complete response rate after induction immunotherapy.
Clinical trial registration: ClinicalTrials.gov ( NCT05149170 )
... PD-L1 positivity in tumor cells and immune cells invading the tumor is associated with improved overall survival (OS) [11,12]. There are recent case series demonstrating the effectiveness of PD-1 blockade with pembrolizumab, with a complete response (CR) rate ranging from 29 to 71%; however, response to PD-1 blockade remains equivocal because of small sample sizes [14][15][16]. Biomarkers for predicting the response of NKTCL patients to immune checkpoint inhibitors (ICIs) have not been identified. In this context, we report the largest study evaluating the efficacy and safety of pembrolizumab, in 59 patients, for R/R NKTCL from 13 tertiary institutes in Korea. ...
Purpose:
PD-1 blockade with pembrolizumab has shown promising activity in relapsed/refractory (R/R) extranodal natural killer (NK)/T-cell lymphoma (NKTCL), but studies are limited, with small patient numbers.
Materials and methods:
Thirteen institutes involved with the Consortium for Improving Survival of Lymphoma, a Korean lymphoma study group, collected the clinical data of 59 patients treated with pembrolizumab as salvage therapy between 2016 and 2022.
Results:
The median age of the patients was 60 years (range, 22 - 87), and 76.3% had advanced Ann Abor stage disease. Pembrolizumab was given to 35.6%, 40.7%, and 23.7% of the patients as second-, third-, and fourth- or higher-line chemotherapy, respectively. The overall response rate was 40.7%, with 28.8% having complete response. The estimated 2-year progression-free survival (PFS) and overall survival (OS) rates for all patients were 21.5% and 28.7%, respectively; for responders, the rates were 53.0% and 60.7%, respectively. Although not statistically significant, Eastern Cooperative Oncology Group performance status ≥ 2 (hazard ratio [HR], 1.91; 95% confidence interval [95% CI], 0.93-3.94, p=0.078) and stage III or IV disease (HR 2.59; 95% CI 0.96-6.96, p=0.060) were associated with a trend toward shorter PFS in multivariate analysis. Grade 3 or 4 adverse events (AEs) were noted in 12 patients (20.3%); neutropenia (10.2%), fatigue (6.8%), and pneumonitis (5.1%) were most common AEs.
Conclusion:
In conclusion, while pembrolizumab had a modest effect on patients with R/R NKTL, it may be a useful salvage therapy for patients with localized disease and good performance status.
... [7,8] Most recently, novel therapeutic regimes such as immune checkpoint inhibitors and histone deacetylase inhibitors have demonstrated beneficial outcomes for advanced or relapsed/refractory NKTCL, but only for a limited proportion of patients. [9][10][11][12][13][14] These varied behaviors and treatment responses highlight the intrinsic heterogeneity of NK-TCL. ...
Extranodal natural killer/T‐cell lymphoma (NKTCL) is an aggressive type of lymphoma associated with Epstein–Barr virus (EBV) and characterized by heterogeneous tumor behaviors. To better understand the origins of the heterogeneity, this study utilizes single‐cell RNA sequencing (scRNA‐seq) analysis to profile the tumor microenvironment (TME) of NKTCL at the single‐cell level. Together with in vitro and in vivo models, the study identifies a subset of LMP1⁺ malignant NK cells contributing to the tumorigenesis and development of heterogeneous malignant cells in NKTCL. Furthermore, malignant NK cells interact with various immunocytes via chemokines and their receptors, secrete substantial DPP4 that impairs the chemotaxis of immunocytes and regulates their infiltration. They also exhibit an immunosuppressive effect on T cells, which is further boosted by LMP1. Moreover, high transcription of EBV‐encoded genes and low infiltration of tumor‐associated macrophages (TAMs) are favorable prognostic indicators for NKTCL in multiple patient cohorts. This study for the first time deciphers the heterogeneous composition of NKTCL TME at single‐cell resolution, highlighting the crucial role of malignant NK cells with EBV‐encoded LMP1 in reshaping the cellular landscape and fostering an immunosuppressive microenvironment. These findings provide insights into understanding the pathogenic mechanisms of NKTCL and developing novel therapeutic strategies against NKTCL.
... Natural killer/T-cell lymphoma (NKTCL) is a subtype of Epstein-Barr virus-related non-Hodgkin lymphoma common in Asia and Latin America but rare elsewhere [1]. Although gratifying progress has been made in the treatment of NKTCL, the poor prognosis of refractory/relapsed (R/R) NKTCL still presents a therapeutic challenge due to its resistance to traditional chemotherapy drugs [2,3]. ...
The treatment of natural killer/T-cell lymphoma (NKTCL) presents an onerous challenge, and a search for new therapeutic targets is urgently needed. Poly ADP-ribose polymerase inhibitors (PARPi) were initially used to treat breast and ovarian cancers with BRCA1/2 mutations. Their excellent antitumor efficacy led to a series of clinical trials conducted in other malignancies. However, the exploration of PARPi and their potential use in combination treatments for NKTCL remains unexplored. We treated NKTCL cell lines with fluzoparib (a novel inhibitor of PARP) and chidamide (a classical inhibitor of HDACs) to explore their cytotoxic effects in vitro. Then, their antitumor efficacy in vivo was confirmed in YT-luciferin xenograft mouse models. Fluzoparib or chidamide alone inhibited NKTCL cell proliferation in a dose-dependent manner. Cotreatment with both drugs synergistically induced excessive accumulation of DNA double-strand breaks and massive apoptotic cell death by inhibiting the DNA damage repair pathway, as shown by the decreased protein levels of p-ATM, p-BRCA1, p-ATR, and Rad51. Moreover, the combination treatment apparently increased the level of intracellular reactive oxygen species (ROS) to enhance apoptosis, and pretreatment with an ROS scavenger reduced the proapoptotic effect by 30–60% in NKTCL cell lines. In vivo, this combined regimen also showed synergistic antitumor effects in xenograft mouse models. The combination of fluzoparib and chidamide showed synergistic effects against NKTCL both in vitro and in vivo and deserves further exploration in clinical trials.
