Charlie Swanton: Treating cancer

Over the last 5–10 years, researchers in various labs have been studying bacteria that appear to be associated with cancers, particularly those prone to metastasise or spread. Is this just a side effect because an abnormal cell is attracting bacteria, or are the bacteria actively contributing? Some researchers suggest these bacteria may even cause resistance to certain chemotherapies, essentially helping the cancer cells...

Charlie – Yes, I think this is a very interesting and rapidly emerging area of study, with evidence steadily building to support that idea. Let’s start with a well-established bacterial cause of cancer: Helicobacter pylori (H. pylori), which is a very common cause of gastric cancer.

We know, thanks to the work of Barry Marshall and others—who won the Nobel Prize—that H. pylori directly causes gastric cancer. Over the last five years or so, it has also emerged that another bacterium, a so-called PKS-positive E. coli, can cause mutations in the gut. These mutations likely help initiate the early stages of cancer by triggering genetic changes in cells and enabling other tissue inflammatory mediators to drive cancer’s invasive steps.

As you rightly mentioned, we’ve also reported in recent years the association between the gut microbiome and differential responses to therapy, as well as the presence of bacteria within tumour cells. What we currently lack is clear functional evidence of exactly how these processes work. It’s undoubtedly complex. For instance, how does a gut microbe influence the peripheral immune response to therapy? How could it activate or suppress, depending on the type of bacteria, the cellular T-cell response to immunotherapy in distant locations such as the bloodstream or the lungs, far from the gut?

Understanding these processes is challenging, and gathering definitive evidence will take time—but progress is happening quickly. I think this will be a very hot area of research over the next five years.

Chris – Some people describe the microbiome as a hidden organ that we’ve overlooked for far too long. There are around 50 trillion bacteria in the average human gut, secreting a wide array of molecules into our circulation. For example, John Cryan in Ireland has shown that the microbiome is even involved in forming the blood-brain barrier in a developing baby during pregnancy. If it can produce those kinds of signals, it doesn’t seem far-fetched that manipulating the microbiome could influence cancer.

Charlie – I completely agree. If there’s one thing science has taught me over the last 20 years, it’s that you have to believe in what seems impossible. Things that feel like science fiction today often become science fact tomorrow.

Take cancer as an example. Twenty years ago, I didn’t think of it as a systemic disease. Now we know that tumour cells interact broadly with the body. They communicate with the liver to alter metabolism, break down muscle and fat to create building blocks for growth, and even influence neuronal networks. It’s a systemic disease interacting with multiple organs—and the same can likely be said for the microbiome.

Chris – Let’s talk about managing or treating cancer. Understanding the mechanisms of a disease is crucial for developing treatments because it shows us how to disrupt its processes. What have been the major breakthroughs in cancer treatment, especially once the snowball is already rolling?

Charlie – That’s a big question! If we focus on the major advances over the last two decades, during my career in medicine, I’d highlight two game-changing developments.

First, the advent of targeted therapies. These are treatments—small molecules or antibodies—that specifically target abnormalities in cancer cells. For example, mutations in certain genes or overexpression of proteins on the cell surface allow cancer cells to proliferate.

A well-known example is the HER2 oncogene in breast cancer, targeted by the antibody Herceptin. Another example is Imatinib, which targets specific kinases in chronic myeloid leukaemia (CML). These therapies attack the cancer cells while sparing normal cells and have transformed cancer treatment.

The second major breakthrough, without a doubt, is immunotherapy. When I was training in the 1990s, many researchers had given up hope of boosting the immune system to fight cancer. Funding was withdrawn, and the field stalled. But then Jim Allison and Tasuku Honjo showed that there are “brakes” on the immune system—CTLA-4 and PD-1—that can be targeted with antibodies. By releasing these brakes, T-cells can recognise and attack cancer cells.

Clinical trials led by people like James Larkin at the Royal Marsden demonstrated this beautifully in melanoma patients. Today, we’re talking about curing metastatic melanoma, even in cases where it has spread to the brain. Immunotherapies that target PD-1 and CTLA-4 are transforming outcomes.

I vividly remember in 2005 sitting with Professor Martin Gore, a brilliant oncologist, as he lamented how little progress had been made in melanoma treatment during his 40-year career. But within 18 months, the first immunotherapy trials produced spectacular results. Patients achieved long-term remission, and the approach revolutionised how we manage the disease almost overnight.

This is what gives us hope. What seems impossible today can become possible tomorrow. It’s a message of hope for patients and a reminder to all of us in medicine to keep pushing forward.