Promoting Response to IMmunotherapy by Exercise in Patients With Advanced Renal Cell Carcinoma

There is strong evidence from randomized controlled trials that exercise during cancer treatment can maintain physical fitness, limit fatigue, and enhance health-related quality of life (HRQoL). Some studies also showed that exercise may help patients to better tolerate their treatment. However, most exercise trials have been conducted in patients receiving chemotherapy or radiotherapy, and little is known about the feasibility or effects of exercise during immunotherapy, particularly in patients with advanced RCC.

First-line treatment for patients with advanced RCC often consists of dual ICI treatment with nivolumab plus ipilimumab. While this combination has shown to improve survival, a substantial proportion of patients do not respond, and approximately 44% experience any grade immune-related adverse events. Tumor hypoxia, an immunosuppressive tumor microenvironment, and insufficient infiltration of cytotoxic immune cells are key factors believed to contribute to treatment resistance.

Preclinical studies in mice have shown that aerobic exercise can positively influence the tumor microenvironment through reduced tumor hypoxia, enhanced tumor perfusion, and increased activity and infiltration of cytotoxic immune cells such as CD8+ T cells and natural killer (NK) cells, while reducing immunosuppressive cell populations. In addition, preclinical studies in mice suggested that exercise-induced changes in the gut microbiome can further support immune activation and improve responses to immunotherapy. Despite this promising biological rationale, no clinical studies have evaluated whether supervised exercise is feasible or beneficial in patients with advanced RCC.

The primary objective of this pilot randomized controlled trial is to evaluate the feasibility of a supervised exercise program during first-line dual ICI therapy in patients with advanced RCC. Secondary objectives are to explore the preliminary effects of exercise on immune phenotype and function, inflammatory markers, circulating tumor (ct)DNA, gut microbiome composition, body composition, aerobic fitness, muscle function, physical activity, and patient reported outcomes including HRQoL, fatigue, anxiety, depression, sleep, and diet. In addition, changes in immune function, gut microbiome composition and clinical outcomes will also be explored.

This study is a two-arm randomized controlled trial including 30 adult patients with advanced RCC. Participants will be randomized to the intervention arm that receives a supervised HIIT program in addition to usual care or to a usual care control arm. The intervention consists of two supervised 60-minute HIIT-exercise sessions per week, delivered by oncology trained physiotherapists, combined with one additional home-based moderate intensity exercise session of at least 30 min per week. The intervention starts with the first cycle of immunotherapy and continues for four treatment cycles. Blood and stool samples will be collected at baseline and at 6 weeks and 12 weeks during treatment to assess immune and microbiome changes. In addition, in participants allocated to the exercise intervention group, to evaluate the acute effects of exercise on the immune response, blood samples will be collected immediately before and after a supervised exercise session.

Physical fitness tests, questionnaires and Fitbit to monitor physical activity will be used to evaluate functional and patient-reported outcomes.

This pilot study will provide important information on the feasibility of exercise during immunotherapy and generate preliminary data on potential immunological effects. These findings will inform the design of future larger trials aimed to optimize supportive care and improve treatment outcomes for patients with advanced RCC.

• Body composition [Time frame: 12 weeks (Baseline, post-intervention)]
• Estimated aerobic fitness [Time frame: 12 weeks (Baseline, post-intervention)]
• Lower body muscle function [Time frame: 12 weeks (Baseline, post-intervention)]
• Physical activity [Time frame: 12 weeks (Baseline, post-intervention)]
• Health-related quality of life (HRQoL) [Time frame: 12 weeks (Baseline, post-intervention)]
• Fatigue [Time frame: 12 weeks (Baseline, post-intervention)]
• Anxiety and depression [Time frame: 12 weeks (Baseline, post-intervention)]
• Sleep [Time frame: 12 weeks (Baseline, post-intervention)]
• Diet [Time frame: 12 weeks (Baseline, post-intervention)]
• ctDNA [Time frame: 12 weeks (baseline, 6 weeks, and post-intervention)]
• Immune cell phenotype and function, and inflammatory markers [Time frame: 12 weeks (baseline, 6 weeks, and post-intervention)]
• Gut microbiome composition [Time frame: 12 weeks (baseline and post-intervention)]