Whole-genome sequencing identifies responders to Pembrolizumab in relapse/refractory natural-killer/T cell lymphoma

Lim, Jing Quan; Huang, Dachuan; Tang, Tiffany; Tan, Daryl; Laurensia, Yurike; Peng, Roujun; Wong, Esther Kam Yin; Cheah, Daryl Ming Zhe; Chia, Burton Kuan Hui; Iqbal, Jabed; Grigoropoulos, Nicholas F.; Nairismagi, Maarja-Liisa; Ng, Cedric Chuan Young; Rajasegaran, Vikneswari; Hong, Huangming; Kim, Seok Jin; Cho, Junhun; Tse, Eric; Mow, Benjamin; Cai, Qing-Qing; Poon, Limei; Cai, Qingqing; Tan, Jian; Chan, Jason Yongsheng; Lim, Jimmy; Goh, Yeow Tee; Phipps, Colin; Rötzschke, Olaf; Cheng, Chee Leong; Ha, Jeslin Chian Hung; Khoo, Lay Poh; Loh, Yvonne; Au-Yeung, Rex; Chan, Thomas S. Y.; Kwong, Yok–Lam; Hwang, William Ying Khee; Kim, Won Seog; Bei, Jin‐Xin; Lin, Tongyu; Ong, Choon Kiat; Lim, Soon Thye

doi:10.1038/s41375-020-1000-0

Cited by 58 publications

(52 citation statements)

References 14 publications

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“…Further retrospective studies have supported this reported efficacy and prospective trials are underway [87]. Recent data published have demonstrated via whole-genome sequencing that structural alterations of PD-L1 are seen in patients with NK/T-cell lymphoma who respond to pembrolizumab [88].…”

Section: Checkpoint Inhibitorsmentioning

confidence: 68%

Targeted Approaches to T-Cell Lymphoma

Harrop

Abeyakoon

Weyden

et al. 2021

JPM

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The T-cell lymphomas are a rare group of Non-Hodgkin’s lymphomas derived from mature T-lymphocytes. They are divided broadly into the Peripheral T-cell lymphomas and the Cutaneous T-cell lymphomas. Clinical outcomes vary widely but are generally unsatisfactory with current treatments. The development of an understanding of the various critical pathways in T-cell lymphogenesis and subsequent identification of therapeutic targets has led to a rapid expansion of the previously underwhelming T-cell lymphoma armament. This review aims to provide an up-to-date overview of the current state of targeted therapies in the T-cell lymphomas, including novel antibody-based treatments, small molecule inhibitors and immune-based therapies.

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Section: Checkpoint Inhibitorsmentioning

confidence: 68%

Targeted Approaches to T-Cell Lymphoma

Harrop

Abeyakoon

Weyden

et al. 2021

JPM

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“…Relapse/refractory NKTCL patients who failed previous chemotherapies were treated with pembrolizumab, and the response was favorable. Four out of seven patients responded to the treatment and the adverse effects were tolerable [86] . Whole-genome sequencing on 19 refractory/relapsed NKTCL patients receiving pembrolizumab showed that the structural rearrangement of the PD-L1 gene (PD-L1 MUT ) disrupting the 3'-UTR was the only gene variation in tumor samples of patient who had response to pembrolizumab in contrast with nonresponders.…”

Section: Overexpressed and Mediates Proliferation And Migration In Vitromentioning

confidence: 93%

Genetics and genomics of extranodal natural killer/T cell lymphoma: from etiology to treatment

Jiang¹,

Ruan²,

Wang³

et al. 2021

jtgg

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Extranodal natural killer/T cell lymphoma (NKTCL) is a heterogenous and unique epidemiological non-Hodgkin's lymphoma, which is strongly associated with Epstein-Barr virus (EBV) infection. Based on the development of various sequencing methods and molecular biology technologies, genome-and transcriptome-wide association studies of NKTCL have provided insight into the etiology and pathogenesis of NKTCL. Comparative genomic hybridization detected variations in tumor suppressor genes such as PRDM1, RUNX3, and EZH2. Whole-exome sequencing identified pathogenic variant such as DDX3X, and TP53. Signal pathways such as the Janus kinase/signal transduction and activator of transcription pathway and nuclear factor kappaB pathway are frequently abnormal in NKTCL. In addition, programmed death-1, programmed death ligand-1, and the human leukocyte antigen risk alleles are significantly associated with NKTCL pathogenesis. Meanwhile, epigenetics analysis has also exposited changes such as PTPRK, HACE1, microRNAs, and long non-coding RNAs, which play important role on the development and biology of NKTCL. EBV infection is tightly correlated with NKTCL. Viral genomic alterations and lytic genes of EBV are reported to have pathogenic effects on host cells that contribute to the etiology of NKTCL. We summarize the genomic and genetic alterations during the pathogenesis and development of NKTCL and exhibit the potential therapeutic targets that are worth exploring in future research and clinical trials.

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“…EGR1 expression was highest in the immune-tolerant group and tended to decrease in the order of immune evasion-A, immune evasion-B, and immune-silenced subgroups, suggesting that EGR1 contributes to early tumorigenesis by suppressing the immune response [ 110 ]. A retrospective multicenter clinicopathologic and genetic analysis of patients with relapsed or refractory NKTCL treated with pembrolizumab identified cryptic rearrangements of the PD-L1 gene disrupting the 3′-UTR to be a more reliable biomarker of the response to pembrolizumab than the immunohistochemical staining of membranous PD-L1 on NKTCL tumoral cells [ 16 ].…”

Section: Current Treatment Strategies For Nktcl and Potential Predictive Biomarkersmentioning

confidence: 99%

Towards Next Generation Biomarkers in Natural Killer/T-Cell Lymphoma

Chan

Lim

Ong

2021

Life

Self Cite

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Natural killer/T-cell lymphoma (NKTCL) is an Epstein–Barr virus-associated non-Hodgkin lymphoma linked to an aggressive clinical course and poor prognosis. Despite an improvement in survival outcomes with the incorporation of novel agents including immune checkpoint inhibitors in the treatment of NKTCL, a significant proportion of patients still relapse or remain refractory to treatment. Several clinical prognostic models have been developed for NKTCL patients treated in the modern era, though the optimal approach to risk stratification remains to be determined. Novel molecular biomarkers derived from multi-omic profiling have recently been developed, with the potential to improve diagnosis, prognostication and treatment of this disease. Notably, a number of potential biomarkers have emerged from a better understanding of the tumor immune microenvironment and inflammatory responses. This includes a recently described 3′UTR structural variant in the PD-L1 gene, which confers susceptibility to checkpoint immunotherapy. In this review, we summarize the biomarker landscape of NKTCL and highlight emerging biomarkers with the potential for clinical implementation.

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Whole-genome sequencing identifies responders to Pembrolizumab in relapse/refractory natural-killer/T cell lymphoma

Cited by 58 publications

References 14 publications

Targeted Approaches to T-Cell Lymphoma

Targeted Approaches to T-Cell Lymphoma

Genetics and genomics of extranodal natural killer/T cell lymphoma: from etiology to treatment

Towards Next Generation Biomarkers in Natural Killer/T-Cell Lymphoma

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