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Lucy Denly

DPhil, Jenner Institute

Improving immunotherapy by defining the interaction between the bacterial vaccine BCG and the host epigenomic and immune response

I am undertaking a DPhil investigating the non-specific immunological and epigenetic effects of the Bacille Calmette-Guérin (BCG) vaccine, which is used to immunize against tuberculosis and is also used as immunotherapy in the treatment of non-muscle invasive bladder cancer. I am particularly interested in the epigenetic changes induced by BCG leading to the phenomena of ‘trained immunity’, and how this may relate to the anti-tumour effects of the vaccine. Amongst other techniques, I will be using TAPS (Tet-assisted pyridine borane sequencing), a new technique developed in the Ludwig Institute, to investigate patterns of DNA methylation in immune and bladder tissue.

How could this research ultimately benefit patients?

BCG treatment reduces recurrent rate and prevents progression of bladder cancer in around 60% of treated patients. However, the non-responsive patients have poor prognosis and high morbidity. Hence there is an unmet clinical need to stratify patients for BCG treatment as well as to understand why the remaining 40% of bladder cancer patients fail to benefit from BCG treatment. Defining the molecular mechanism(s) and durability of these non-specific effects would allow us to stratify patients with bladder cancer who are most likely to respond to BCG, develop more specific interventions and minimise the side effects of BCG. Understanding these mechanisms would also better inform us as to whether BCG based therapy can be adopted to treat cancer types other than NMIBC. 

About Lucy

Prior to my DPhil, I had just completed my 4th year as a medical student at Oxford Medical School. As an undergraduate student I was particularly interested in immunology, however I had not done much laboratory-based immunology before starting my DPhil. 

What does your DPhil experience look like day-to-day?

What my day looks like can vary widely and this is something I really love about my DPhil. There are some days that my time is entirely devoted to sample collection– this may involve being in surgical theatres or BCG clinic, which is where patients receive their treatment, and then some hours processing and documenting these samples. Some days I am running experiments and may spend many hours in the lab doing TAPS or flow cytometry. More recently, I am spending more and more time in front of my computer trying to get some code to run for bioinformatics analysis. Usually, I have a number of meetings each week too –with my supervisors, collaborators and my lab groups - and seminars put on within my Department. 

If you had to name one thing, what is your greatest achievement since starting your DPhil?

I think the achievement I am most proud of during my DPhil so far has been my setting up of the clinical study that I am running, following patients with bladder cancer being treated with BCG immunotherapy. At the start of my DPhil, it felt like an unrealistically mammoth goal that I was not prepared for, however through hard work, resilience, and lots of help from supportive colleagues, the trial has slowly evolved into a reality. This process has taught me a very varied set of skills that I hope will be useful in my future career, ranging from patient-facing clinical skills, through to the logistics of trial management, laboratory-based biochemistry and now bioinformatics.

Accolades and Key Publications

One idea that has been borne out of my DPhil project is investigating the urine collected as part of the clinical study for non-invasive biomarkers of tumour recurrence. I successfully applied for a £25k grant from OxCODE to fund some pilot data for this work and am working on analysis of the data this grant funded. I also enjoyed attending a summer school on Early Detection run by the International Alliance for Early Detection (ACED) and won the prize for Best Group Presentation for proposal of a potential biomarker for early detection of cancer.