​Predicting how a patient will respond to treatment is one of the most important areas of study in cancer research. By accurately predicting how a patient responds to treatment, can help save time and cost as well as improve their survival rate.

Natural-killer T-cell lymphoma (NKTCL), is a type of non-Hodgkin lymphoma which is prevalent in Asia. It is a type of aggressive blood cancer for which there are currently no targeted therapy options. Standard treatment is a combination of chemotherapy and radiotherapy. However, patients often relapse and face very poor prognosis. The three-year overall survival rate is under 30 per cent for high-risk patients.

With these stats in mind, a team led by clinician-scientists and researchers from the National Cancer Centre Singapore (NCCS) embarked on a study to better predict treatment response for patients with NKTCL. They discovered a genetic link that better predicts treatment response for relapsed/refractory patients with NKTCL. The landmark study was recently published in high-impact factor journal, Leukemia.

The NCCS team embarked on this study in 2016, when a group of clinicians from Singapore and Hong Kong observed that some relapsed/refractory NKTCL patients responded well to Pembrolizumab, an anti-PD-1 monoclonal antibody, which is a form of immunotherapy commonly used to treat lung cancer, when standard treatment was no longer effective.

Encouraging responses were observed with some patients eventually achieving complete remission with no trace of detectable cancer. This very positive observation led the team to delve into a deeper study of the use of anti-PD-1 therapy in NKTCL patients.

The team performed whole-genome sequencing, to identify a mutation in PD-L1 gene as a reliable biomarker to identify patients with a high likelihood of positive response to anti PD-1 therapy. Before this discovery, the study of how NKTCL patients respond to immunotherapy had been limited.

Dr Ong Choon Kiat, Principal Investigator, Division of Cellular and Molecular Research (CMR) – Lymphoma Genomic Translational Laboratory, NCCS shared, "we are pleased that our study has identified robust biomarkers to reliably improve treatment selection for patients who will have a high likelihood of responding positively to PD-1 therapy. This is especially important for advanced-stage NKTCL patients who usually have very poor outcomes and succumb to the disease despite multiple lines of salvage therapies.”

“Being able to identify a treatment that works would ultimately improve effective response, save cost and prevent patients from being exposed to unnecessary side effects of salvage therapies,” added Dr Ong.

What the study found

The team sequenced the whole genome of the patients’ pre-pembrolizumab treated tumours and studied their molecular profile. Upon discovering a structural alteration in the patient’s PD-L1 gene, they worked with collaborators in Singapore and countries including China, Hong Kong and South Korea to study more patients treated with pembrolizumab.

A total of 19 relapsed/refractory patients were studied. An overall response of 47% (9/19) was observed, of which 7 achieved complete response with no trace of cancer detected in their blood and/or bone marrow. The gene alteration was found amongst 4 out of the 7 patients who responded favourably to pembrolizumab.

A patient’s first-hand experience

One of the patients, Mr Ng* (not his real name) was diagnosed with NKTCL in 2018 at the age of 69 years old. Upon diagnosis, he received chemotherapy and went into remission, before the cancer relapsed in 6-9 months later. His relapsed tumor was tested positive for the biomarker, PD-L1 mutation.

“I was given the option to receive pembrolizumab and after two cycles, the scan showed that all the cancer cells had disappeared, and I am now back in remission,” shared Mr Ng.

Mr Ng elaborated that “It is through the NCCS team’s hard work and perseverance that I could receive this therapy and go into remission. I’m really thankful for the second chance I have at getting my life back.”

“Seeing patients achieving complete response always bring joy to my work as a researcher and is a constant encouragement to keep striving harder. It is a constant reminder of why I do research,” shared Dr Ong.

Ensuring the results to benefit more patients

In 2017, SingHealth, the public healthcare cluster which NCCS is a part of, filed a patent for the discovery, which was a result of the team’s research on this genome response. A licensing agreement with Lucence Diagnostics has enabled the biotech company to develop this technology into a diagnostic test, to determine which patients will benefit from the targeted treatment. Development of this clinical assay has been completed and is ready for deployment.

Professor Lim Soon Thye, Deputy Group Chairman Medical Board, SingHealth; Deputy Medical Director, NCCS (Clinical); Senior Associate Dean, MD Programmes, Duke-NUS Medical School and Principal Investigator of the study said, “Guiding the choice of therapy is critical for cancer patients, where treatment must be timely and drugs can be costly. It is not easy to bridge the gap from bench to bedside, so it is particularly gratifying to be able to translate our findings into clinical applications that will directly benefit patients and healthcare systems.”

The study is a multi-institutional and multi-national level effort involving Singapore, China, Hong Kong and South Korea. Besides NCCS, several local institutions such as National University Hospital, Singapore General Hospital, Agency for Science, Technology and Research (A*STAR) are also involved.

In NCCS, the study team includes medical oncologists who specialise in treating lymphomas as well as a team of scientists from the Lymphoma Genomic Translational Laboratory.

The NCCS team now plans to embark on further studies to explore the extended use of the assay for other cancer types, including prostate, ovarian and lung cancer.