Exercise as a Tool to Improve Response to Immunotherapy in Non-small Cell Lung Cancer

Overview

This project is about the effect of a 12-week training therapy intervention in patients suffering from non-small cell lung cancer. It has widely been accepted that exercise is preventive against certain types of cancer. Individuals following an active lifestyle have a significantly lower risk for several chronic diseases, including cancer, as compared to sedentary ones. However, evidence is still lacking for exercise as part of routine cancer treatment (as it has already been implemented routinely in patients with heart disease, for example). In this study, patients suffering from non-small cell lung cancer undergo either a 12-week training program consisting of moderate-intensity continuous exercise (MICE), or a 12-week program with high-intensity interval exercise. Both groups will be compared to a control group receiving standard exercise recommendations. The response to immunotherapy, measured by the radiologic therapy response, will be the main endpoint. Additionally, blood will be taken from the patients at different timepoints, and blood samples will be tested for immunologic changes. FACS analysis will be used to assess the properties of immune cells and potential changes upon the exercise regimen. Mitochondrial function will be assessed via the Seahorse machine, and mass spectrometry (lipidomics) will be used for the analysis of lipid profile changes.

Lung cancer is the number one cause of cancer-related deaths worldwide. A few decades ago, the prognosis at lung cancer first diagnosis was generally poor with only a few months of median survival. New immunotherapy treatment regimens have markedly improved survival times - especially in certain histologic and molecular pathologic subtypes. The positive effect of exercise on the incidence of several cancer entities such as colorectal- or breast cancer, has been demonstrated previously. Physically active individuals are diagnosed with cancer significantly less often as compared to sedentary people. In oncologic follow-up care, a positive effect of exercise and training with an advantage in survival has also been proven, e.g. in breast cancer patients. In addition, existing data shows a positive effect of exercise on the immune system: active individuals show a different pattern of proinflammatory markers in the blood serum, with every exercise session generating an immune-stimulatory effect which changes the immunologic serum profile also at rest. Thus, regular exercise has an anti-inflammatory long-term effect. Hypothesis and Objectives: With our project we seek to demonstrate a possible benefit on immunotherapy response upon a medically guided training regimen. Setting and Methods. To exactly define "exercise" in this setting, as a first step we will test two exercise types in healthy individuals. According to their individual exercise capacity as determined by spiroergometry, healthy subjects will either perform moderate-intensity continuous exercise (MICE), or a high-intensity interval training (HIIT). By means of venous blood sampling before and after training we shall determine the respective changes of serum immune markers through exercise. The same two training types will then be performed by lung cancer patients upon immunotherapy, with one patient group doing MICE-sessions, one group doing the HIIT and a third group who will receive general exercise recommendations. Response to therapy and inflammatory serum parameters will be compared between the groups. Exercising patients will be advised to train once a week under medical supervision, and to walk briskly for 30 minutes every day of the week in addition. Our hypothesis is, that exercise should be implemented as a complementary treatment strategy in every oncologic therapy setting, possibly improving not only physical health and wellbeing but also treatment response. In addition to improving the patients' quality of life by a better physical capacity and fitness, helping them in their everyday activities, we propose that the implementation of exercise programs in various oncologic settings in future may improve the patients' outcome. Scientific Novelty. Standardization of exercise regimens in oncologic scenarios in the existing literature is generally poor. We carry out one of the few studies where the type, duration, timing and intensity of exercise in both exercise groups is clearly defined, comparing two different training types to sedentary control patients, respectively. Exercise needs to be seen as a drug, and like in any drug the optimum dose must be clearly outlined. Moreover, we will implement a priming exercise in our study, meaning that patients exercise close to the administration of immunotherapy, hypothesizing that this may further ameliorate therapy response.