Liquid biopsy for aggressive T-cell lymphoma

In the UK, around 500 people every year are diagnosed with aggressive T-cell lymphoma. It is one of the more difficult blood cancers not only to diagnose but also to treat successfully. Only 1 in 2 patients survive beyond 2 years. Currently, T-cell lymphoma patients are treated with chemotherapy. However, up to half of patients will relapse within a year meaning they have received ineffective and toxic treatment. New treatment approaches overcoming resistance to chemotherapy are urgently needed.

A variety of new drugs are now in development which may have activity against T-cell lymphoma. To use these effectively we need to be able to identify chemotherapy resistance early. However, current tests to predict chemotherapy resistance used in the clinic do not exist.

This project aims to apply a new approach called liquid biopsy that has recently shown success in other cancers. Liquid biopsies can detect cancer abnormalities called mutations in blood samples. Because blood samples can be easily repeated, changes in the levels of these mutations early during treatment has been shown to predict patient outcomes in many cancers.

We in Leicester have recently shown that T-cell lymphoma mutations can be successfully detected in the blood of patients using liquid biopsy. We have also shown that sequential blood samples allow us to track these mutations in patients undergoing chemotherapy. These data suggest that liquid biopsy may be a useful tool to predict how patients will respond to treatment.

However, there remain several key gaps that we need to address before liquid biopsies can be used routinely in the clinic, which this project sets out to achieve. Firstly, we plan to improve our liquid biopsy test to ensure it is as accurate as possible. Subsequently, we will examine how well liquid biopsies predict resistance to chemotherapy. The results from liquid biopsies will be compared to CT scan results (how we currently assess treatment response), to allow us to decide which approach performs better. Finally, understanding what happens to T-cell lymphoma mutations in patients who are resistant to chemotherapy will give answers as to why this happens in some patients but not others. These insights will help us develop treatments that match new precision cancer medicines to mutations found in the blood to target each person's T-cell lymphoma individually.

It is possible to answer these questions now for the first time thanks to the UK T-cell lymphoma biobank. This was a national effort, coordinated in Leicester, to collect and store blood and tissue samples from 90 T-cell lymphoma patients. The samples have now been collected and are available for this project.

Taken together, this project aims to take an important step towards liquid biopsies being used in the clinic to help patients and doctors decide together what treatments are most likely to achieve successful clinical outcomes.

Peripheral T-cell lymphoma (PTCL) is characterised by early treatment failure and poor clinical outcomes in many patients. However, existing tools to predict early treatment response are inadequate. This project will develop a robust and quality assured circulating tumour DNA (ctDNA) test. Subsequently, the project will leverage a unique sample repository available through the UK PTCL Biobank to explore the hypothesis that ctDNA analysis predicts clinical outcomes in patients receiving standard first-line chemotherapy. Furthermore, by interrogating serial ctDNA data from patients who experience early relapse this project will identify molecular drivers of chemoresistance in PTCL.

The project is divided into three main work packages (WP):

a) WP1 will develop a robust, quality assured test, to detect and track ctDNA mutations in PTCL. This work will advance our existing PTCL ctDNA assay by incorporating molecular barcoding and error suppression bioinformatics to improve test sensitivity and specificity. Test validation will be performed to UKAS accreditation standards.

b) WP2 will use this test to determine the utility of ctDNA analysis as a predictor of clinical outcomes in PTCL. These data will provide evidence that ctDNA-based clinical outcome prediction is a tool that can support precision medicine approaches in PTCL.

c) WP3 will focus on uncovering molecular dynamics of chemoresistance in PTCL by tracking phased variants to discover clonal shifts and identify molecular drivers underpinning drug resistance. Reverse translating these clinically informed mechanistic insights will accelerate preclinical studies testing therapeutic strategies that overcome chemoresistance.

Collectively, this project aims to demonstrate that ctDNA analysis can act as a precision medicine catalyst in PTCL and lead to improved outcomes in these difficult-to-treat diseases.