A groundbreaking phase 2 clinical trial has revealed promising results for a novel combination therapy targeting extranodal natural killer/T-cell lymphoma (ENKTL), an aggressive and notoriously difficult-to-treat blood cancer prevalent in Asian populations. The multinational effort, involving leading clinicians and scientists from South Korea and Singapore, underscores the power of integrating cutting-edge immunotherapies with advanced genomics to pioneer personalized cancer treatment strategies. First published in the esteemed journal Blood earlier this year, these findings signify a major stride forward in the management of relapsed or refractory ENKTL, a malignancy that until now has lacked approved targeted therapies.
ENKTL is a rare subtype of non-Hodgkin lymphoma, often originating within the nasal cavity or other extranodal sites. This malignancy is distinctively associated with the Epstein–Barr virus (EBV), which is implicated in its pathogenesis. Notably, the disease shows a higher prevalence among East Asian populations compared to Western cohorts, spotlighting the importance of region-specific research and treatment paradigms. Patients with ENKTL who relapse or become refractory to standard chemotherapy face dismal prognoses, highlighting a critical unmet medical need that motivates ongoing scientific inquiry.
Building on years of molecular research at the National Cancer Centre Singapore (NCCS), investigators have leveraged genomic sequencing technologies to decode the genetic underpinnings of ENKTL. In a landmark discovery published in 2020, the NCCS Lymphoma Translational Research Laboratory identified mutations within the PD-L1 gene that disrupt its interaction with PD-1, a critical immune checkpoint pathway. This disruption contributes to immune evasion by tumor cells, suggesting that immune checkpoint inhibitors could restore immune surveillance in affected patients. This key insight provided the biological rationale for incorporating PD-1 blockade into therapeutic regimens.
Expanding on their genomic insights, NCCS researchers employed machine learning algorithms on a dataset of 260 ENKTL patient genomes sourced from Singapore, China, Belgium, and Taiwan. This analysis culminated in the development of a genomic prognostic model based on mutations in 13 genes, capable of predicting patient outcomes with high accuracy. Validated across international cohorts, this prognostic tool has the potential to revolutionize clinical decision-making, enabling more precise patient stratification and individualized therapy selection.
The collaborative synergy between NCCS and South Korea’s Consortium for Improving Survival of Lymphoma (CISL) propelled this translational research into a clinical trial setting. Commencing in 2021, the phase 2 trial enrolled 37 patients across six Korean centers, all diagnosed with relapsed or refractory ENKTL. The trial tested a combination of cemiplimab, a PD-1 immune checkpoint inhibitor, and isatuximab, a monoclonal antibody that targets CD38—a molecule implicated in immune resistance mechanisms. Through intravenous administration up to two years or until disease progression or toxicity occurred, this regimen aimed to tackle the tumor through complementary immunomodulatory mechanisms.
Results from the trial are striking. More than half of the patients, 51%, attained a complete response characterized by over an 80% reduction in tumor burden. An additional 14% achieved partial responses, culminating in an overall objective response rate (ORR) of 65%. The median duration of response was notable at 21 months, underscoring not only the efficacy but also the durability of the combined immunotherapy. These findings shine a beacon of hope for patients historically facing limited treatment options.
Genomic profiling conducted by NCCS validated earlier hypotheses regarding PD-L1 mutations as predictive biomarkers. Intriguingly, all three patients harboring the PD-L1 3’ UTR mutation achieved complete responses, confirming the translational relevance of this mutation for therapeutic responsiveness. Moreover, the prognostic model developed in 2022 was corroborated as a reliable predictor even as treatment landscapes evolve, reinforcing its utility for future clinical application.
Further immunophenotyping shed light on the tumor microenvironment, revealing that responders exhibited unusually elevated levels of regulatory T cells (Tregs). This observation opens a new avenue for biomarker discovery and possible therapeutic targeting. The role of Tregs in modulating anti-tumoral immunity is complex and may represent an additional layer through which ENKTL evades immune eradication.
Experts at NCCS emphasize that the integration of genomic biomarkers with immunotherapeutic strategies exemplifies the future of oncology—where molecular insights guide targeted, effective, and personalized treatment. Associate Professor Ong Choon Kiat, co-author of the study and head of NCCS’s lymphoma research division, noted that linking specific genetic abnormalities to therapeutic outcomes marks a pivotal advancement in understanding and combating ENKTL.
Co-first author Dr. Lim Jing Quan highlighted the critical role of international collaboration and technological innovation, emphasizing how next-generation sequencing and data analytics are crucial in deciphering tumor heterogeneity and resistance mechanisms. This multidisciplinary approach is vital for translating laboratory discoveries into tangible patient benefits.
Looking forward, NCCS researchers continue to probe the genomes of patients who did not respond to the combination therapy, aiming to unveil additional mutations and pathways that could serve as future drug targets. The atypical abundance of regulatory T cells hints at immune evasion mechanisms that may be amenable to novel interventions. Parallel retrospective analyses are underway to further validate the prognostic model and broaden its clinical impact, paving the way for precision oncology in ENKTL.
The successful deployment of cemiplimab and isatuximab combination therapy represents a landmark achievement in lymphoma treatment, potentially reshaping therapeutic standards for relapsed and refractory cases. Beyond its clinical significance, this study exemplifies the immense value of coupling deep molecular profiling with immunotherapy, offering a beacon of hope for patients afflicted by this challenging disease.
The National Cancer Centre Singapore continues to reinforce its position as a center of excellence in cancer research and care. Equipped with state-of-the-art facilities including the Goh Cheng Liang Proton Therapy Centre, NCCS is at the forefront of blending innovative treatment modalities with precision medicine, expanding the horizons of cancer therapeutics regionally and globally.
Subject of Research: People
Article Title: Efficacy of Combined CD38 and PD1 Inhibition with Isatuximab and Cemiplimab for Relapsed/Refractory NK/T-Cell Lymphoma
News Publication Date: 16 April 2025
Web References:
http://dx.doi.org/10.1182/blood.2024027109
References:
Lim, J. Q., Huang, D., Tang, T., et al. (2020). Whole-genome sequencing identifies responders to Pembrolizumab in relapse/refractory natural-killer/T cell lymphoma. Leukemia, 34(12), 3413–3419.
Lim, J. Q., Huang, D., Chan, J. Y., et al. (2022). A genomic-augmented multivariate prognostic model for the survival of natural-killer/T-cell lymphoma patients from an international cohort. American Journal of Hematology, 97(9), 1159–1169.
Image Credits: National Cancer Centre Singapore
Keywords: Extranodal NK/T-cell lymphoma, ENKTL, immunotherapy, cemiplimab, isatuximab, PD-1, CD38, genomic biomarkers, personalized medicine, lymphoma, phase 2 clinical trial, regulatory T cells, NCCS
