IdentifyinG Radiotherapy and ImmunE ResistanCe Mechanisms In Anal CaNcer (GRECIAN)

Background Anal squamous cell cancer (ASCC) is a rare but rapidly increasing cancer, with approximately 1500 new cases in the UK each year.

The UK has led the world in transforming the management of this disease from radical surgery and colostomy to primary concurrent chemoradiotherapy (CRT) through phase II and phase III trials. CRT is the standard of care for the majority of localised anal cancers and is given with curative intent.

The CRUK PersonaLising Anal cancer radioTherapy dOse (PLATO trial) is a flagship clinical platform led by Leeds Clinical Trial Unit comprising three clinical trials for low, moderate and high-risk cancers (ACT3, 4, 5 respectively).

ACT5 concerns patients who have a substantial risk of locoregional failure (20-30%) and will determine whether radiotherapy dose escalation will reduce locoregional failure.

Alternative future treatment strategies are required to reduce this failure rate, including immunotherapy, which has a strong scientific rationale in this context.

Aims Utilising complimentary laboratory expertise across 3 RadNet Centres, this project will identify candidate immune resistance mechanisms and potential biomarkers for locally advanced anal cancer before, during and after CRT through a translational study of serial peripheral blood and tumour samples.

Methods Perform immunophenotyping of peripheral blood mononuclear cells, characterise ctDNA changes and identify soluble cytokines predictive of treatment failure (Leeds) Characterise the baseline immune microenvironment by multiplex IHC to determine if these can be used to predict clinical outcomes (Manchester) Characterise complement system changes to determine if these can be used to predict clinical outcomes (Oxford) How the results of this research will be used Together the data generated on immunophenotyping, cytokine screening and plasma HPV measurements (Leeds), tumour microenvironment profiling (Manchester) and monitoring of complement system changes (Oxford) will provide a multi-layered and rich hypothesis-generating dataset to be explored further in future preclinical and translational studies.

Based on the identified mechanisms, we will be able to better predict treatment failure and clinical outcomes for these patient, identifying possible drug targets to improve these outcomes.

The above work will improve our understanding of anal cancer biology and aid patient selection and stratification for future clinical trials.