Overview
Background Regular exercise can significantly improve physical and mental health during cancer treatment and reduce the time needed in the hospital. Animal studies suggest that exercise training can also reduce the number of cancer cells. For example, exercise training in mice produces more immune cells in the tumour. These immune cells in the tumour contribute to the destruction and reduction of the size of the tumour and are a vital component of effective immunotherapy (cancer treatment that helps your immune system fight cancer).
In humans, exercise training and the immune response in tumours are less understood. Only 1 study has investigated the effect of a single exercise session before surgical removal of the prostate in prostate cancer patients. As the benefits of exercise are gained from weeks/months of exercise, no effect on the immune cells in the tumours were found.
Following our published pre-surgery exercise versus control group assessing fitness changes in patients with oesophageal cancer, we took advantage of access to patient tumour tissues. We used thin slices of their tumour tissue and state-of-the-art methods to detect and visualise immune cells within the tumour. Compared with the controls, the exercise group had significantly more immune cells in their tumours, largely consisting of a critical subpopulation important for killing cancerous cells called CD8+ T cells. CD8+ T cells in tumours are associated with improved survival outcomes.
Critically, we detected positive associations between changes in patient aerobic fitness and the amount of these cells in the tumour. This suggests that if we increase fitness, we can increase the frequency of these cells in the tumour. Therefore, we propose performing a randomised clinical trial to determine the optimum level of exercise patients need to sustain before surgery to produce this improved immune response.
Aims and objectives The trial will aim to understand how this happens and how the entry of immune cells into the tumour changes the environment around a tumour. We are a multidisciplinary team of exercise immunologists, tumour immunologists and clinicians working with the Human Performance Institute at the University of Surrey in collaboration with the Royal Surrey NHS Trust. We are capable of performing this clinical trial and translational research.
How it will be done We will assess immune cell response in blood samples obtained from oesophageal cancer patients before, during and after a moderate-vigorous-intensity or low-intensity 16-week exercise programme. Following the exercise programme, tumour tissue removed at surgery from these patients will be used to investigate the presence and abundance of immune cells. We will use state-of-the-art technologies to identify different immune cell types, their functionality and their distribution within the tumour tissue.
Potential impact A better understanding of this is crucial, as current anti-cancer immune-based therapeutics work best when there is a pre-existing immune response within the patient's tumour. Generating evidence that exercise can improve the immune response against the tumour in patients with oesophageal cancer would provide significant justification for introducing "personalised" exercise programmes to improve immunotherapeutic treatment outcomes.
Description
Oesophageal cancer is one of the most challenging cancers to treat, with low survival rates, even when people receive intensive treatments such as chemotherapy and surgery. New treatment strategies could therefore lead to significant benefits to patients.
One of the most promising new treatments is immunotherapy, which works by "releasing the brakes" on immune cells. Immunotherapy has transformed outcomes in some cancers, but its impact in oesophageal cancer has been modest so far. One important reason may be that many oesophageal tumours contain few active immune cells to begin with. Finding safe, practical ways to ''wake up'' the immune system and draw immune cells into the tumour could make existing treatments more effective.
Exercise is a simple, low-cost option that could help. Exercise programmes are already used before major surgery to improve fitness and help people cope better with treatment. Research in other cancers shows that exercise can increase the number and activity of key immune cells in the blood and, in some cases, inside tumours. Exercise also affects the gut microbiome. This is the community of bacteria and other microorganisms in our intestines, and the chemicals they produce. These microbial products can travel through the bloodstream and shape how the immune system behaves. However, we do not yet know how these changes work together in people with oesophageal cancer receiving chemotherapy.
In this study, people with oesophageal cancer who are due to receive chemotherapy before surgery will be invited to join a supervised exercise programme. All patients will exercise under the guidance of specialist staff while they are on chemotherapy. One group will follow a lower-intensity programme similar to current NHS prehabilitation. The other group will complete higher-intensity sessions, within safe limits. Comparing these two realistic options will allow us to test whether exercise intensity makes a difference.
We will collect blood and stool samples at key time points before and during treatment. From blood, we will measure changes in immune cells and proteins that signal how "switched on" the immune system is. From stool, we will study the gut microbiome and the metabolites (small molecules) they produce. After surgery, we will examine the removed tumour under the microscope to see whether exercise is linked to differences in the number and type of immune cells inside the tumour. By bringing these measurements together, we hope to understand whether more intensive exercise leads to a more immune-active tumour, and how the change in immune cells alongside systemic signalling molecules are related to these states.
Eligibility
Inclusion Criteria:
- Adults with resectable oesophageal adenocarcinoma who are planned for neoadjuvant chemotherapy followed by surgery
Exclusion Criteria:
- Inability to carry out CPET or exercise due to underlying health conditions
- pregnancy
- \<18 years old