Date of Award
2023
Document Type
Thesis - ECU Access Only
Publisher
Edith Cowan University
Degree Name
Doctor of Philosophy
School
School of Medical and Health Sciences
First Supervisor
Elin Gray
Abstract
Immunotherapy has revolutionised the treatment of advanced non-small cell lung cancer (NSCLC) and resulted in a higher response rate, and improved overall survival, with some deriving durable long-term benefits. However, the majority of patients do not derive clinical benefit from immunotherapy and the adverse events associated with this treatment remains challenging, not only due to the significant morbidity that impairs patients’ quality of life but also the additional financial burden on the health system. Currently, the programmed death ligand -1 (PD-L1) tumour proportion score (TPS) and tumour mutation burden (TMB) are the only Food and Drug Administration (FDA) approved biomarkers that identify patients with NSCLC who will benefit the most from anti-PD1/PD-L1 therapy. Both have several limitations. In particular, patients with PD-L1 TPS of less than 1% or low TMB still derive benefit from the immunotherapy and some with high PD-L1 expression ( > 50%) or high TMB will not respond to anti-PD-L1/ PD1 therapies. Additionally, there are no biomarkers approved for clinical use to predict the development of immune related adverse events (irAEs). Therefore, research exploring additional biomarkers that might add value to PD-L1 TPS or be used as an alternative is necessary. Those can be used to guide selection of the appropriate therapy for each patient based on the likelihood of clinical benefit while minimising the risk of developing adverse events.
Genomic human leukocyte antigen (HLA) has an important role in the activation process of the immune system. HLA presents cellular peptides and engages T-cell receptors (TCR) to activate T cells and to induce an immune response to foreign tissue, pathogens or abnormal antigens. Thus, both are central to the anti-tumour response unleashed by the immune checkpoint inhibitors. Recently, the association between genomic HLA-I homozygosity and worse survival outcomes among lung and melanoma patients treated with immunotherapy has been the subject of various studies with differing findings. Additionally, few studies have shown the association between TCR diversity and immunotherapy response and/or survival outcomes. Pre-treatment TCR repertoire is thought to reflect the ability of the immune system to recognise the tumour neoantigens and attack cancer tissue.
The studies in this thesis provide evidence about the association between genomic HLA and circulating pre-treatment TCR repertoire diversity, and clinical outcome among patients treated with immunotherapy alone or in combination with chemotherapy. The thesis is comprised of 6 chapters: a comprehensive literature review with theoretical framework (Chapter 1); four results chapters (Chapter 2-5); and a final chapter with general discussion and future direction (Chapter 6).
The first chapter of the thesis includes an overview of the current immunotherapy treatment available for patients with locally advanced and metastatic NSCLC and PD-L1 as an approved FDA biomarker and its limitations (Chapter 1). The potential role of genomic HLA and the pre-treatment TCR repertoire as biomarkers for clinical outcomes and immune related toxicities (irAEs) was discussed in the context of the current evidence.
Chapter 2 showed that genomic HLA-I, but not HLA-II, homozygosity at one or more HLA-I loci is associated with worse survival among patients with advanced unresectable NSCLC patients treated with single agent immunotherapy in the first- or second-line setting (Chapter 2). This association is more pronounced among patients with high PD-L1 (TPS ≥ 50%). In Chapter 3, it showed that this association is not observed among patients treated with immunotherapy in combination with chemotherapy in the first line setting.
Chapter 4 shows that homozygosity at one or more HLA-I loci was found to be protective against the development of irAEs. We confirmed that the development of irAEs seems to be associated with a favourable clinical benefit rate (CBR), progression free survival (PFS) and overall survival (OS).
Finally, the role of pre- treatment TCR repertoire diversity and its association with clinical outcomes and irAEs were highlighted in Chapter 5. TCR diversity was assessed using multiple variables. However, only the number of unique clones was found to be correlated with improved CBR among patients treated with pembrolizumab in the first line setting. All the investigated variables; increased number of unique clones or Shannon diversity, reduced evenness or convergence; were individually associated with improved PFS among patients treated with pembrolizumab in combination with chemotherapy. A model score incorporating all four TCR diversity variables was associated with PFS among patients treated with pembrolizumab alone and with CBR and OS among those treated with pembrolizumab in combination with chemotherapy.
Chapter 6 provides a general discussion of the studies covered in this thesis, their key findings in the context of the current literature and their limitations. The role of non-invasive biomarkers as potential biomarkers for patients treated with immunotherapy is highlighted and future studies towards validation and clinical implementation are proposed. Overall, Genomic HLA-I might be more informative among patients treated with immunotherapy alone compared to pre-treatment TCR diversity role, which is more pronounced among those treated with immunotherapy in combination with chemotherapy.
DOI
10.25958/56aa-sh78
Recommended Citation
Abed, A. (2023). Genomic HLA and pre-treatment TCR repertoire as non-invasive biomarkers of clinical outcome to immunotherapy in advanced non-small cell lung cancer patients. Edith Cowan University. https://doi.org/10.25958/56aa-sh78