Genomic analysis provides insight into underpinnings of new treatment combination for deadly, Asian-prevalent lymphoma

Singapore, 16 April 2025 – A multinational research team of clinicians and scientists from South Korea and Singapore has published positive findings from a phase 2 clinical trial for a new combination therapy for an aggressive, Asian-prevalent blood cancer, extranodal NK/T-cell lymphoma. Published in the journal Blood in March 2025, the study not only shows promising patient response to the novel therapy, but also validates genomic biomarkers and a prognostic model previously developed by the National Cancer Centre Singapore (NCCS). Findings point to the potential for more precise and personalised treatment of the disease.

What is ENKTL and how do we treat it?

Extranodal NK/T-cell lymphoma (ENKTL) is a rare subtype of non-Hodgkin lymphoma that typically develops within the nasal cavity. Almost always associated with Epstein–Barr virus (EBV), ENKTL is more prevalent among East Asian populations than in Western populations. Prognosis is poor for patients who relapse and there is no approved targeted therapy to manage these patients. This highlights the urgent need for new and better treatment strategies.

The Lymphoma Translational Research Laboratory at NCCS has been studying the origin and cause of lymphoma, including ENKTL, with a focus on translating genomic discoveries into clinical applications. In 2020, the team discovered that some NK/T-cell lymphoma patients have a mutation in the PD-L1 gene that causes it to bind abnormally to the PD-1 gene, affecting the immune system’s ability to attack cancer cells. By treating these patients with PD-1 targeting immunotherapy, this interaction could be blocked to restore normal anti-tumoural immune system function.[1]

Building on these insights, in 2022, the NCCS team used next-generation sequencing data of 260 ENKTL patients from Singapore, China, Belgium and Taiwan to unravel the genetics of ENKTL. Using machine-learning methods, they identified mutations in 13 genes that built a genomic prognostic model to predict clinical outcomes for ENKTL patients.[2] The model has been tested in subsequent studies to confirm its application and usefulness in real-world clinical settings.

New combination therapy show promise

In 2019, during an international lymphoma conference in Lugano, Switzerland, NCCS researchers met with clinician-scientists from South Korea also studying ENKTL. This meeting marked the beginning of a collaboration that merged complementary strengths – the Korean team led the clinical trials through the Consortium for Improving Survival of Lymphoma (CISL), while the NCCS team contributed deep genomic expertise and analysis capabilities.

In 2021, CISL initiated a phase 2 clinical trial (registered as NCT04763616 at www.clinicaltrials.gov) investigating a new therapeutic combination using cemiplimab, an anti-PD1 immune checkpoint inhibitor, and isatuximab, a monoclonal antibody that targets CD38, a protein implicated in immune resistance. Between 2021 to 2023, 37 patients aged 20 to 68 with relapsed ENKTL were enrolled across 6 sites in South Korea. Patients received intravenous cemiplimab and isatuximab for up to 2 years, or until severe side effects were experienced or disease progressed. Of the 37 patients, 19 or 51% achieved a complete response, with over 80% reduction in tumour volume. Five additional patients (14%) achieved a partial response, or a 20% reduction of tumour volume. Combined, 24 out of 37 patients responded to treatment with an overall objective response rate of 65%. Among responders, the median duration of response was 21 months.

Validating genomic markers and models

Genomic sequencing and analysis were conducted by the Lymphoma Translational Research Laboratory at NCCS.

Notably, all three patients with the genetic mutation, disrupting the 3’UTR of PD-L1, achieved complete response to the combination therapy, reinforcing NCCS’ earlier findings in 2020. The study also validated the 2022 NCCS-developed genomic prognostic model, confirming its utility, robustness and relevance for clinical use, even as treatment paradigms evolve for lymphoma.

Further immmunoprofiling of patients’ samples also revealed responders having unusually high levels of regulatory T cells (Tregs), suggesting a potential new biomarker that could be targeted in future treatment strategies.

Future directions

"The key breakthrough in this study is that we have linked specific genetic markers to treatment response. Our genomic insights help explain why some patients respond well while others do not, paving the way for more targeted and effective treatments in the future,” said Associate Professor Ong Choon Kiat, Head of the Division of Cellular and Molecular Research at NCCS, Head of the Lymphoma Translational Research Laboratory and co-author of the Blood study.

“At the National Cancer Centre Singapore, one of our strengths is understanding the disease at a molecular level and applying cutting-edge sequencing and analysis techniques. This allows us to interpret tumour behaviour in a way that can directly guide treatment choices. Collaborations like this are key to translating scientific insights into real-world patient impact,” said co-first author of the Blood study, Dr Lim Jing Quan, Senior Research Fellow at NCCS.

NCCS researchers are continuing to analyse the tumour genome of trial participants who did not respond, to identify additional therapeutic targets. They postulate that the abnormally high level of Tregs, and possibly other genetic mutations, could suppress anti-tumoural immunity. Meanwhile, additional retrospective studies are planned to validate the broader clinical application of the genomic prognostic model to guide personalised treatment selection for ENKTL.

About the National Cancer Centre Singapore

The National Cancer Centre Singapore (NCCS) is a leading national and regional tertiary cancer centre with specialists who are experts in treating cancer. In addition to offering holistic and multidisciplinary oncology care, our clinicians and scientists collaborate with local and international partners to conduct robust, cutting-edge clinical and translational research. To achieve its vision of being a global leading cancer centre, NCCS offers world-class care and shares its depth of experience and expertise by training local and overseas medical professionals.

To meet growing healthcare needs, the new NCCS building opened in 2023 with increased capacity and expanded facilities dedicated to cancer care, rehabilitation, research and education. To give patients the best treatment outcomes, advanced and innovative treatment such as proton therapy is offered at the new Goh Cheng Liang Proton Therapy Centre at NCCS.

[1] Lim, J. Q., Huang, D., Tang, T., Tan, D., Laurensia, Y., Peng, R. J., Wong, E. K. Y., Cheah, D. M. Z., Chia, B. K. H., Iqbal, J., Grigoropoulos, N. F., Nairismägi, M. L., Ng, C. C. Y., Rajasegaran, V., Hong, H., Kim, S. J., Cho, J., Tse, E., Mow, B., Cai, Q. C., … Lim, S. T. (2020). Whole-genome sequencing identifies responders to Pembrolizumab in relapse/refractory natural-killer/T cell lymphoma. Leukemia, 34(12), 3413–3419. https://doi.org/10.1038/s41375-020-1000-0.

[2] Lim, J. Q., Huang, D., Chan, J. Y., Laurensia, Y., Wong, E. K. Y., Cheah, D. M. Z., Chia, B. K. H., Chuang, W. Y., Kuo, M. C., Su, Y. J., Cai, Q. Q., Feng, Y., Rao, H., Feng, L. N., Wei, P. P., Chen, J. R., Han, B. W., Lin, G. W., Cai, J., Fang, Y., … Ong, C. K. (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. https://doi.org/10.1002/ajh.26636