Characterising the effects of acute exercise on monoclonal antibody immunotherapy efficacy in human haematological cancers

: (Alternative Format Thesis)

Abstract

Cancer is the second leading cause of death worldwide. Globally, 19 million new cases of cancer and 10 million cancer related deaths were reported in 2020, and it is predicted that the cancer cases per year will increase to 28 million by 2040. As the incidence of cancer increase, so too does the economic burden, with a predicted, estimated global cost of $25.3 trillion dollars between 2020 and 2050. Several modifiable risk factors are suggested to reflect this growth, including physical inactivity. Arising in blood and lymphoid tissues, haematological cancers are the fourth most common cancers in the UK, with chronic lymphocytic leukaemia (CLL) and myeloma being the second and third most common haematological cancers in the UK, respectively. Despite the advancements in the treatment landscape of CLL and myeloma, particularly since the advent of monoclonal antibody (mAb) immunotherapy over the last two decades, these cancers remain uncurable.

This is partly due to the failure of different mechanisms-of-action of these mAbs including: (i) antibody-dependent cellular cytotoxicity (ADCC), (ii) complement-dependent cytotoxicity (CDC), and (iii) antibody-dependent cellular phagocytosis (ADCP), coupled with cancer cells that persist in protective microenvironments in the body. These persistent cells – commonly referred to as minimal residual disease (MRD) – survive treatment, ultimately resulting in cancer relapse. Rituximab, an anti-CD20 mAb used to treat CLL, and daratumumab, an anti-CD38 mAb used to treat myeloma, harness the host immune system to eliminate cancer cells in the body. It is well established that an individual bout of exercise at a moderate to vigorous intensity induces profound changes to immune cell kinetics in healthy humans, such as a 1,000% increase in natural killer (NK)-cells which are utilised by mAb immunotherapies to eliminate cancer cells via ADCC. However, it is currently unknown how an individual bout of exercise influences the immune system in people with haematological cancers, and whether any changes to immune cell kinetics can improve the efficacy of mAb immunotherapy.

The aim of this thesis was to characterise the effects of an individual (acute) bout of moderate intensity exercise on the frequency of leukocytes in people with CLL and myeloma, and to determine whether any changes to leukocyte frequency affect the efficacy of rituximab and daratumumab, respectively.

In Chapter 3, a narrative review was conducted to summarise the different mechanisms-of-action of mAbs used to treat B-cell haematological cancers in the UK, describe the mechanisms-of-resistance of these mAbs, and discuss how exercise might be harnessed to overcome these mechanisms-of-resistance.

In Chapter 4, we found that moderate intensity cycling for 30-minutes increased the frequency of CLL cells and cytotoxic NK-cells in blood, and resulted in enhanced NK-cell mediated killing of autologous CLL cells in the presence of rituximab in patients with CLL ex vivo.

In Chapter 5, we found that moderate intensity cycling for 30-minutes increased the frequency of cytotoxic NK-cells and monocytes, resulting in enhanced daratumumab mediated ADCC against a myeloma cell line in patients with myeloma in vitro. However, no changes were observed in the frequency of circulating myeloma cells, and an elevation was observed for NK-cells expressing the daratumumab target, CD38, which may be more susceptible to elimination via daratumumab-mediated ADCC.

Finally, in Chapter 6, we found that 45-minutes of flat, or downhill running in healthy humans did not alter blood C1q – a protein which activates mAb-mediated CDC – or subsequent CDC activity of rituximab or daratumumab against haematological cancer lines in vitro.

This thesis shows that an individual bout of moderate intensity exercise induces changes to immune cell kinetics in people with haematological cancers, which resulted in enhanced ADCC activity by therapeutic mAbs, whilst no effect was found for CDC activity in healthy humans. Additionally, this thesis highlights the heterogeneity in the clinical course of haematological cancers and their treatment with mAb immunotherapy, and proposes that the optimal timing, dose, and frequency of exercise, alongside the half-life of mAb immunotherapies should be taken into careful consideration. Thus, exercise as an adjuvant to mAb immunotherapy should not be considered a one-size-fits-all in haematological cancers.

Date of Award	27 Mar 2023
Original language	English
Awarding Institution	University of Bath
Supervisor	John Campbell (Supervisor) & James Turner (Supervisor)