Title: Harnessing the immuno-stimulatory effects of acute exercise to enhance the detection and treatment of minimal residual disease in chronic lymphocytic leukaemia.
Funder: Cancer Research UK

Abstract: Background: Anti-CD20 immunotherapies have greatly improved complete response rates in Chronic Lymphocytic Leukaemia (CLL), yet, minimal residual disease (MRD) remains an intractable problem that commonly eventuates in disease relapse. MRD is the persistence of treatment-resistant cancer cells that are undetectable at the time of treatment response determination, owing to the diffuse spread of CLL cells within the protective microenvironment of the lymphoid tissues. To improve detection and treatment of MRD, we propose a highly-novel approach: acute exercise. Acute exercise induces a dramatic redeployment of immune cells from lymphoid tissues into blood, and we propose that this redeployment can be harnessed to improve: (i) the detection of MRD, and (ii) the depth of CLL response to live immunotherapy infusion. Aims: This Pioneer Award aims to generate proof of concept data showing that acute exercise can enhance (i) MRD detection: by examining how acute exercise affects CLL frequency in blood, measured regularly throughout 6 months of treatment, and (ii) the efficacy of CLL immunotherapy: by examining the impact of acute bouts of exercise on immunotherapy-induced CLL cell death, measured in vitro, throughout 6 months of treatment. Methods: Blood will be collected from people with CLL before and during bouts of exercise, conducted monthly throughout 6 months of chemoimmunotherapy treatment. Blood will be analysed by flow cytometry, revealing how exercise affects tumour and immune cells. Using an in vitro model – that combines primary tumour cells, immune cells and anti-CD20 immunotherapy – we will establish how acute bouts of exercise affect the efficacy of CLL immunotherapy. How results will be used: These results will inform the viability of: (i) a large RCT evaluating exercise as a method to enhance the sensitivity of MRD detection, and (ii) a phase-1/2 trial piloting the safety and preliminary efficacy of acute exercise conducted during live anti-CD20 immunotherapy infusion.

Lay abstract: Background: Anti-CD20 immunotherapies have greatly improved complete response rates in Chronic Lymphocytic Leukaemia (CLL), yet, minimal residual disease (MRD) remains an intractable problem that commonly eventuates in disease relapse. MRD is the persistence of treatment-resistant cancer cells that are undetectable at the time of treatment response determination, owing to the diffuse spread of CLL cells within the protective microenvironment of the lymphoid tissues. To improve detection and treatment of MRD, we propose a highly-novel approach: acute exercise. Acute exercise induces a dramatic redeployment of immune cells from lymphoid tissues into blood, and we propose that this redeployment can be harnessed to improve: (i) the detection of MRD, and (ii) the depth of CLL response to live immunotherapy infusion. Aims: This Pioneer Award aims to generate proof of concept data showing that acute exercise can enhance (i) MRD detection: by examining how acute exercise affects CLL frequency in blood, measured regularly throughout 6 months of treatment, and (ii) the efficacy of CLL immunotherapy: by examining the impact of acute bouts of exercise on immunotherapy-induced CLL cell death, measured in vitro, throughout 6 months of treatment. Methods: Blood will be collected from people with CLL before and during bouts of exercise, conducted monthly throughout 6 months of chemoimmunotherapy treatment. Blood will be analysed by flow cytometry, revealing how exercise affects tumour and immune cells. Using an in vitro model – that combines primary tumour cells, immune cells and anti-CD20 immunotherapy – we will establish how acute bouts of exercise affect the efficacy of CLL immunotherapy. How results will be used: These results will inform the viability of: (i) a large RCT evaluating exercise as a method to enhance the sensitivity of MRD detection, and (ii) a phase-1/2 trial piloting the safety and preliminary efficacy of acute exercise conducted during live anti-CD20 immunotherapy infusion.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS