John Cairns: Pages 3, 9

DEVELOPING NEW TOOLS IN THE FIGHT AGAINST CANCER

MARTIN FELLERMEYER OXFORD THATCHER SCHOLAR

Martin Fellermeyer is a third year doctoral student and Oxford Thatcher Scholar based at the Weatherall Institute of Molecular Medicine. We visited him there to learn more about his work developing life-saving cancer therapies, and how the support of the Margaret Thatcher Scholarship Trust has galvanised his work both in and outside the laboratory. Unlike a virus or bacterial infection, cancer is an intrinsic pathology: it arises due to problems with our own cells. Considering that the human body consists of around 37 trillion cells, any of which can develop into a tumour cell, it didn’t take long for me to become fascinated as an undergraduate by the mechanisms of how our body stops the ‘natural’ build-up of cancer cells. Most importantly, I came to believe that understanding these processes could translate into more effective drugs to treat patients in the clinic – this was the starting point for all my research.

Generally, a cancerous cell is one of our own cells that developed mutations in its genetic material (the DNA), which lead to changes and perturbations of the cell’s behaviour, most importantly an increase in cell divisions that allows the tumour to grow. Luckily, there are different ‘self-defence’ systems in our body that aim to prevent exactly this from happening.

Firstly, our cells are constantly scanning themselves for injuries, such as missing or broken DNA, and seeking to repair themselves. If a cell is unable to repair itself, it will voluntarily die in order to prevent further damage to the body. That is why developing cancer cells seek not only to increase growth rate through DNA mutations, but also to manipulate DNA damage detection machinery and prevent cell suicide.

Secondly, if a cell’s intrinsic protection mechanisms fail, there are also extrinsic mechanisms in place to reduce the chance of tumour development. Most importantly, immune cells travel through our body looking for ‘different’ cells, including cancerous ones. A developing tumour will always seek ways to evade these protection mechanisms.

Conventional chemotherapy is not designed to support these protection mechanisms with much accuracy: it simply kills all quickly growing cells, leading to the familiar side effects of hair loss and gastrointestinal problems as gut and hair cells are also targeted due to their fast cell growth. That is why there has been a lot of interest in finding drugs that target the different protection mechanisms of our own body in an effort to ‘re-activate’ them.

that will bind and block to what are known as the ‘stop signals’ used by cancerous cells to prevent immune cells from attacking them.

Our immune system works by maintaining a delicate balance of rapidly and effectively eliminating threats (e.g. viruses, bacteria, cancerous cells) and keeping our body intact by not interfering with normal processes (e.g. microbiota in the gut and on the skin). The problem with cancer is that a developing tumour utilises immune-stopping factors to disrupt this process, either by sending immune cells away or dramatically reducing their killing functions. In particular, some tumour cells use a ‘stop signal’ on their surface to prevent the patrolling immune cells from identifying them as a threat and killing them.

Martin in his lab at the Weatherall Institute

Consequently, there has been a huge effort from the scientific community to find drugs that block the different ‘stop signals’ so immune cells can function as usual and eradicate the cancer. The first drug based on this idea was approved in 2011 (ipilimumab), leading to the 2018 Nobel Prize in Physiology or Medicine for the two scientists who facilitated this discovery.

My research looks to build on this work by developing novel drugs that will bind and block the ‘stop signals’, thereby unleashing the power of our immune cells. As mentioned, there is a great variety of immune cells in our body, all with very specific functions. In my first project, I am testing new drug combinations that focus on the ‘re-activation’ of different immune cells, aiming to create an improved therapy as compared to only activating one type of immune cell. In the second part of my project, I am re-engineering existing drugs that are used in the clinic to make them more effective in their blockade of the ‘stop signal’. I am deeply grateful to the Margaret Thatcher Scholarship Trust for enabling me to come to this inspiring city and carry out the research for my DPhil. The financial support allows me to follow my passions, both through my research and outside the lab.

Giving something back has always been important to me – and not merely through my work. In the first months of my DPhil, I trained as a peer supporter, offering mental health support to students in Somerville and the Medical Sciences Division. Shortly after, I became vice president of a new University-wide peer support initiative and, when Covid-19 hit, I started delivering hot meals on a weekly basis to local households in need of support. Finally, I was elected this year as president of the Graduate Student Association at my institute, following a term as welfare officer. There I hope to be able to have a positive influence on the academic and social environment for my peers.

It’s a privilege to do this work here in Oxford, and I hope it makes a difference.