Graham, Rebecca N.; (2022) Investigating the immunostimulatory role of mesenchymal stromal cells in the treatment of lung cancer. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Lung cancer is the leading cause of cancer death worldwide. Current treatments fail to offer a cure and are accompanied by a heavy burden of side effects, highlighting the need for novel therapies. The homing capacity of mesenchymal stromal cells (MSCs) offers an opportunity to deliver therapies directly to the tumour, overcoming the toxicities of systemic drugs. MSCTRAIL is a novel anti-cancer therapeutic which employs allogeneic umbilical cord MSCs to deliver TNF-Related Apoptosis-Inducing Ligand (TRAIL); this is being investigated in a phase I clinical trial for patients with lung adenocarcinoma. However, allogeneic MSCs are not inert vehicles and are known to have immunomodulatory properties. With their growing use in cancer therapy, it is crucial to understand the dynamics of the cells following delivery and if these could be harnessed to enhance anti-tumour efficacy. This study aimed to characterise the immunological phenotype of MSCTRAIL and elucidate the interactions of the therapy with cells of the immune system. The work presented here combines phenotyping of MSCTRAIL, in vitro functional assays and analysis of research samples from patients treated with MSCTRAIL. I show that MSCTRAIL has the potential to promote monocyte recruitment and differentiation, and data suggest that the cells may support polarisation to a pro-inflammatory function within the tumour microenvironment. This, in turn, could enhance the killing of cancer cells. I further demonstrate that MSCTRAIL lacks the expression profile required for direct allorejection and does not elicit a detectable immune response in patients (n=5). In addition, I develop tools for the detection of circulating MSCTRAIL and immune monitoring of these patients. These data are important to the further development of MSCTRAIL as a novel treatment modality. In addition, the findings carry implications for the wider, expanding field of MSC-based therapies for cancer, currently hampered by a lack of clinical data. Finally, the tools developed here will be valuable in the assessment of immunogenicity and immune monitoring of patients in further clinical trials of cellular therapies.

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