Haematology

Determinants of response to immunotherapeutic strategies in aggressive lymphomas

Supervisors: Dr Matthew Ahearne (mja40@leicester.ac.uk), Dr Harriet Walter (hw191@leicester.ac.uk)  and Professor Martin Dyer (mjsd1@leicester.ac.uk)

Targeting of tumour antigens with T cell engagers is a recognised cancer treatment strategy in B cell malignancies. Whilst CD20xCD3 bispecific antibodies and CD19 CAR T-cell therapies have transformed clinical outcome in relapsed/refractory disease, the clinical determinants of response and optimal sequencing strategies remain unknown.  Multiple studies are ongoing to assess activity in combination and in earlier treatment settings.

Additional studies are required to understand how target antigen expression affects response and how antigen loss through cell surface remodelling and/or mutations can result in resistance. Importantly, the tumour cell surface is central to interactions with the microenvironment and is thus key to diagnosis, biological understanding, and revealing new strategies for immunotherapeutic strategies. 

Aligning to existing workflows and outputs from the Dyer/Walter/Ahearne laboratory, the Fellow will explore longitudinal dynamic changes in target antigen expression during treatment using multi-omic approaches.   The following methodologies will be applied:

• Multicolour flow cytometry
• Unbiased cell surface proteomics
• Imaging of the immune synapse
• RNA sequencing
• WES

The Fellow will have the opportunity to enhance and apply computational skills by working with pre-collected datasets, data generated from wet lab experiments, and clinical datasets, all of which can be aligned with their specific skills, experience, and interests.

Liquid biopsy for aggressive lymphoma

Supervisors: Dr Matthew Ahearne (mja40@leicester.ac.uk), Dr Harriet Walter (hw191@leicester.ac.uk)  and Professor Martin Dyer (mjsd1@leicester.ac.uk)

Improving outcomes in aggressive lymphoma requires tools to detect and track molecular changes during therapy, enabling early prediction of therapy response and the implementation of precision medicine strategies.

Circulating tumour DNA (ctDNA), often called “liquid biopsies”, shows significant promise for non-invasive molecular profiling. Liquid biopsies can be easily repeated during therapy, allowing treatment to be tailored to individual patients.

Building on Leicester’s established expertise in ctDNA, our research aims to develop and validate novel ctDNA-based tests to predict lymphoma relapse, identify mechanisms of resistance, and personalize lymphoma treatment. An ongoing ctDNA project in T-cell lymphoma, supported by recent MRC funding, will also extend to a further study starting in 2025 focused on improving the diagnosis of lymphoma in acutely unwell patients using liquid biopsy techniques.

The successful Fellow will leverage these and other ctDNA datasets to investigate several key research themes, including:

• Clinical utility of liquid biopsy versus conventional diagnostic testing.
• Modelling clinical risk prediction using longitudinal analysis
• Enhanced ctDNA detection through computational enrichment
• Integration of multi-modal ctDNA detection approaches (mutation panel, shallow whole genome, methylation)

The research plan can be tailored to align with the Fellow’s specific interests and skill set. This project will enable the Fellow to generate preliminary data, forming the foundation of a PhD/MD fellowship.