Development of less-invasive predictive biomarkers of immunotherapy treatment in patients with non-small cell lung cancer (NSCLC) and genitourinary cancer

Abstract

My PhD research project was a prospective ‘cohort’ study across 2 institutions within South West Sydney Local Health District (SWSLHD) (Liverpool and Macarthur Cancer Therapy Centres). Patients newly commencing ICI therapy +/- chemotherapy for advanced NSCLC, RCC and urothelial/bladder cancers were recruited and provided samples across a 12-month period whilst on treatment for biomarker analysis. Chapter 1 is the Introduction describing the current state of biomarker research in the context of ICI therapy, the treatment of NSCLC, RCC and urothelial bladder cancer, as well as the thesis aims, rationale and general overview. Chapter 2 is the Study Design; an overview of the prospective ‘cohort’ study. Chapter 3 is a retrospective review of 450 patients treated with ICIs in SWSLHD from 2011-2020. We used univariate and multivariable analysis to evaluate patient, disease and treatment characteristics in addition to irAEs to determine correlation with response and survival outcomes. Chapter 4 examines tissue-based biomarkers from patients recruited during the prospective study using immunohistochemistry (IHC) to evaluate PD-L1 expression, tumour infiltrating lymphocytes (TILs), novel DNA damage/inflammation markers apoptosisassociated speck-like protein containing a CARD (ASC) and stimulator of interferon genes (STING), as well as targeted next generation sequencing (NGS) to look at TMB. Chapter 5 analyses peripheral blood mononuclear cells (PBMCs) collected from patients during the prospective study; mass cytometry was used to characterise the changes in the peripheral immune system in response to treatment and identifies key immune subsets that may predict patient response to ICI therapy. Chapter 6 examines peripheral blood circulating cytokine levels collected from patients during the prospective study; flow cytometry was used to evaluate their association with treatment response. Chapter 7 examines the gut microbiome by 16S rRNA for bacteria and internal transcribed spacer (ITS) for fungus sequencing of stool samples provided by patients during the prospective study. And finally, Chapter 8 discusses the overarching results, potential for combining biomarkers from different aspects of the thesis, how this work is situated in the current literature and key future directions for the field.

Date of Thesis submission	2023
Original language	English
Awarding Institution	Western Sydney University
Supervisor	Tara Roberts (Supervisor), Therese Becker (Supervisor), Wei Chua (Supervisor), Victoria Bray (Supervisor), Slade Jensen (Supervisor) & Soon Lee (Supervisor)