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Biomarker Linked to Prediction of Positive Response to Immunotherapy

Researchers from the National Cancer Centre Singapore (NCCS) discover a genetic marker that identifies patients of aggressive blood cancer likely to respond well to a novel immunotherapy treatment for natural-killer T-cell lymphoma.

A team led by clinician-scientists and researchers from the National Cancer Centre Singapore (NCCS) have discovered a genetic link to better predict a positive treatment response for patients with relapsed or refractory natural-killer T-cell lymphoma (NKTCL). By performing whole-genome sequencing, the team identified that mutation in the PD-L1 gene is a reliable biomarker for identifying lymphoma patients who are highly likely to respond positively to anti PD-1 therapy (a type of immunotherapy), which has shown promising therapeutic results.

These landmark findings, recently published in Leukemia, were prompted by the observations of a group of clinicians from Singapore and Hong Kong in 2016 who realised that some patients with relapsed or refractory NKTCL responded very well to pembrolizumab when the standard treatment was no longer effective.

NKTCL is a type of non-Hodgkin lymphoma prevalent in Asia which currently has no targeted therapy options. The standard treatment for this rare and aggressive type of blood cancer is a combination of chemotherapy and radiotherapy. Unfortunately, the prognosis for those with NKTCL is poor, with many suffering relapses and the three-year overall survival rate being under 30 percent for high-risk patients.

However, when treated with permbrolizumab, an anti-PD-1 monoclonal antibody commonly used to treat lung cancer, positive responses were observed with some patients achieving complete remission with no trace of detectable cancer.

Encouraged by this, the team embarked on a deeper study into the use of anti-PD-1 therapy in NKTCL patients. They sequenced the whole genome of a patient’s tumours before they were treated with pembrolizumab and studied their molecular profile. Upon discovering a structural alteration in their PD-L1 gene, the team worked with collaborators from Singapore’s Agency for Science, Technology and Research (A*STAR), Genome Institute, and investigators from China, Hong Kong, and South Korea, to study more NKTCL patients with pembrolizumab.

Out of the total of 19 relapsed/refractory patients studied, a favourable response of 47 percent (9/19) was observed, with 7 patients achieving complete remission. No traces of cancer were detected in their blood or bone marrow. The PD-1 gene alteration was found in 4 of these 7 patients.

Regarding this breakthrough, Dr Ong Choon Kiat, Principal Investigator, Division of Cellular and Molecular Research (CMR) – Lymphoma Genomic Translational Laboratory, NCCS said, “The study of how NKTCL patients respond to immunotherapy has been limited to date. We are pleased that our study has identified robust biomarkers that reliably improve treatment selection for patients who will have a high likelihood of responding positively. This discovery of PD-L1 gene as a reliable response indicator was made possible with the participation of our patients and collaboration with multi-site partners.”

In 2017, Singhealth (the public healthcare cluster that includes NCCS) filed a patent for this technology and signed a licensing agreement with Lucence Diagnostics to develop it into a diagnostic test. The biotech company has since completed developing a clinical assay for determining which patients will benefit from targeted treatment with pembrolizumab. According to Dr Tan Min-Han, the founding CEO and Medical Director of Lucence Diagnostics, the test is ready for deployment and will be progressively made available in Asia and the United States.

Professor William Hwang, Medical Director, National Cancer Centre Singapore said, “This significant bench-to-bedside translation will provide patients with this aggressive form of blood cancer with significant benefits in terms of health outcomes and cost savings. We are gratified to work with partners like Lucence Diagnostics who are developing test kits that will improve clinical outcomes and reduce healthcare costs for patients globally.”

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. [APBN]