Precision Medicine in Immunotherapy and Lung Cancer

Background This thesis will explore various techniques and methods to advance the goal of precision therapy in clinical oncology, encompassing tumour-specific and treatment-specific methods. It explores tumour-specific treatment such as platinum chemotherapy or immunotherapy for non-small cell lung cancer, and combines potential biomarkers from simple immunohistochemistry to advanced single-cell RNA sequencing data to predict immunotherapy toxicity. Outline The first chapter of this thesis explores the role of immunohistochemistry markers for Activin-A, GDF-11 and TGF-B as potential predictive biomarkers for platinum-based chemotherapy within two populations – a retrospective cohort from Westmead Hospital and a prospectively-collected biobank (EnRICH) across New South Wales. The second and third chapters explore potential mechanisms and biomarkers for immunotherapy-induced toxicity. A pilot experiment with eight patients with severe immunotherapy toxicity and eight controls analysed single-cell RNA sequencing data generated from peripheral blood mononuclear cells (PBMCs) and identified key differentially expressed genes of interest. A deeper analysis of associated single nucleotide polymorphisms (SNPs) affecting specific gene expression led to the development of a predictive polygenic risk score for the onset of immunotherapy-related toxicity. The final chapter explores two validation experiments performed to confirm the scRNA-seq findings. The first is a flow cytometry protein quantification experiment to investigate whether differential protein-coding gene expression led to similar differences in protein expression. The second study explores specific single nucleotide polymorphisms associated with the key differentially expressed genes within a large prospectively collected cohort of lung cancer patients, to identify potential germline risk factors for the development of immunotherapy toxicity. Summary Although personalised oncology has been an important goal for the last decade, our ability to pursue this in the clinic is limited by relevant biomarkers and robust clinical evidence to support their use. This thesis explores various avenues to support the development of pre-treatment biomarkers for treatment efficacy (platinum chemotherapy) or immune-related adverse events from checkpoint inhibitor immunotherapy.

Grantor dc:publisher

UNSW, Sydney

Year dc:date

2026

Author dc:creator

• Lim, Jennifer ; https://orcid.org/0000-0001-6953-8085

• Cancer
• Immunotherapy
• Biomarkers
• Treatment toxicity
• anzsrc-for: 321109 Predictive and prognostic markers
• anzsrc-for: 321107 Liquid biopsies
• anzsrc-for: 321104 Cancer therapy (excl. chemotherapy and radiation therapy)

Statement dc:rights

• open access
• CC BY 4.0
• free_to_read

Licence

• https://purl.org/coar/access_right/c_abf2
• https://creativecommons.org/licenses/by/4.0/

Language dc:language

en

Identifier

https://doi.org/10.26190/unsworks/32246

OAI identifier oai:identifier

oai:unsworks.library.unsw.edu.au:1959.4/107712