Immunological biomarkers of outcome in thoracic cancers

    Research output: ThesisDoctoral Thesis

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    Abstract

    Chemotherapy is the mainstay of treatment for patients with malignant pleural mesothelioma (MPM) and advanced non-small cell lung cancer (NSCLC). More recently, targeted therapies have demonstrated efficacy in a subset of patients with NSCLC harbouring an oncogenic driver, such as epidermal growth factor receptor (EGFR) mutations. However, most patients with NSCLC do not have an actionable mutation, or have mutations for which no treatment is available. Moreover, those with a driver mutation who are treated with a targeted agent and achieve an initial response, invariably develop resistance.

    In recent clinical developments, immune checkpoint inhibitors against the programmed death receptor-1 (PD-1) are now approved for the treatment of NSCLC and malignant melanoma, with ongoing trials in most solid tumours. Although some patients achieve durable responses, most do not respond to single-agent immunotherapy. Moreover, there are no reliable biomarkers to identify patients more likely to respond to treatment. The expression of PD-ligand-1 (PD-L1) on tumour cells has been the most promising biomarker, but remains unreliable as some patients with PD-L1-negative tumours also respond to PD-1 blockade, possibly due to the dynamic nature of PD-L1 expression.

    Following these important therapeutic developments, there are ongoing efforts to develop strategies that may improve efficacy by combining an immunotherapy with other immunotherapies, or with conventional therapies, including chemotherapy, targeted therapies, and radiotherapy. Understanding the effects of individual therapies on the immune system will enable the development of rational approaches to optimise therapeutic sequencing and combinations. Furthermore, there is an urgent need to identify biomarkers to individualise treatment decisions and maximise the likelihood of response.

    This thesis describes two studies in MPM and NSCLC. The first was a retrospective study of 274 patients with advanced MPM, examining the prognostic significance of the neutrophil-to-lymphocyte ratio (NLR), a marker of systemic inflammation, compared to routinely collected clinical and laboratory variables. NLR was previously reported as a promising biomarker that was predictive of survival in MPM and other solid tumours. Although this study aimed to validate NLR as a biomarker in MPM, it was not found to be prognostic on univariate or multivariate analysis for the total cohort or on subgroup analyses. In contrast, established prognostic variables, including age, histology, performance status, weight loss, chest pain and platelet count were independent predictors. Therefore, although the prospect of a simple blood test providing prognostic information was promising, it did not withstand the rigour of independent validation in this cohort.

    The second study examined the effects of EGFR tyrosine kinase inhibitors (TKIs) on the immune system in a prospective cohort of patients with advanced NSCLC. 33 patients receiving an EGFR-TKI were recruited, including 12 patients with a known EGFR mutation. Peripheral blood mononuclear cells were collected pre-treatment, and after 1, 3 and 8 weeks, and flow cytometry was used to identify immune cell subsets. Four panels were used to examine proportions of effector CD8+ and regulatory CD4+ T cells, dendritic cells (DCs), and PD-1 and PD-L1 expression on T cells and DCs. Immune parameters were correlated with radiological response, progression-free survival (PFS), and overall survival (OS).

    Compared to healthy donors, patients were found to have higher proportions of proliferating T cells at baseline, suggesting the presence of an underlying immune response. After commencement of an EGFR-TKI, there were no significant changes in immune cell subsets across the four study time-points. In the subset of patients who subsequently developed progressive disease, there was a significant increase in the proportions of PD-L1+ T cells after one week of EGFR-TKI. Moreover, the proportion of PD-L1+ T cells at one week was strongly associated with radiological response, PFS, and OS, independently of other variables, including EGFR mutation status.

    This was the first study to assess the effects of EGFR-TKIs on the immune system in patients with advanced NSCLC. Although no significant longitudinal changes in immune parameters were revealed, the finding that higher proportions of PD-L1+ T cells was associated with worse clinical outcomes, is important. Although the results are exploratory in nature, they support the concept that peripheral immune parameters may be a non-invasive surrogate for an anti-tumour response in this cohort, and warrant further investigation. Furthermore, relationships between clinical outcomes and proportions of PD-L1+ T cells should be prospectively examined as a predictive biomarker for anti-PD-1 therapies.

    Original languageEnglish
    QualificationDoctor of Philosophy
    Supervisors/Advisors
    • Nowak, Anna, Supervisor
    • Lake, Richard, Supervisor
    • Millward, Michael, Supervisor
    • McDonnell, Alison, Supervisor
    Publication statusUnpublished - 2016

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