Risk Factors of Immune-ChEckpoint Inhibitors MEdiated Liver, Gastrointestinal, Endocrine and Skin Toxicity

Summary

Participation Requirements

Description

Immune-checkpoint inhibitors (ICIs) represent a major breakthrough in clinical oncology. ICIs are monoclonal antibodies targeting extracellular proteins CTLA-4 (cytotoxic T lymphocytes associated antigen-4) and PD-1 (Programmed cell death-1) with its ligands PD-L1/PD-L2. Their binding promotes T cel...

Immune-checkpoint inhibitors (ICIs) represent a major breakthrough in clinical oncology. ICIs are monoclonal antibodies targeting extracellular proteins CTLA-4 (cytotoxic T lymphocytes associated antigen-4) and PD-1 (Programmed cell death-1) with its ligands PD-L1/PD-L2. Their binding promotes T cell activation via T cell receptor pathway, resulting in upregulation of CD8+ T cell cytotoxicity. Activated cytotoxic T cells recognise and attack cancer cells, thus inhibiting cancer progression and development. ICI therapy has been clinically validated to be highly effective and has tailored treatment guidelines for melanoma, non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC). However, high incidence of specific immune-related adverse events (irAEs) requires further understanding of the cellular and molecular mechanisms involved in the efficacy and side effects of ICI therapy. Non-coding RNA (ncRNA) is gaining increased traction, as a mechanism of gene regulation. 70% of the human genome is transcribed into ncRNA which was disregarded for decades, being considered "junk DNA". Craig Mello and Andrew Fire discovered its ability to post-transcriptionally interfere with gene expression, thus diminishing expression of proteins. With regard to ICI therapies, ncRNAs have been shown to modulate the expression of immune checkpoints. Moreover, specific ncRNAs are significantly associated with survival rates of NSCLC patients treated with nivolumab, albeit without an established mechanism. Thus, there is a clear association between ncRNAs and ICI, however the precise mechanisms underlying ICI therapy response, immune activation, and adverse events remain unknown. This study will examine coding and non-coding transcriptomes to better understand the transcriptional regulation of ICI response. Aims. To establish ncRNAs significantly associated with ICI response and irAEs To establish immune cell phenotypes associated with ICI response and irAEs To establish mechanisms responsible for this association To identify potential therapeutic targets which may inhibit aforementioned mechanisms This is a prospective multicentre cohort study. Investigators aim to enrol cancer patients who are scheduled to receive ICI therapy at one of the participating study sites. Participants will be divided into three groups: (1) ICI treatment only; (2) ICIs in combination with platinum-based chemotherapy; (3) ICIs in combination with tyrosine kinase inhibitors. It is planned to recruit a minimum of 60 patients for groups 2, 3 and minimum of 80 patients within the group 1 (ICI monotherapy: n=40; combined ICI therapy: n=40) giving a minimum total cohort of 200 patients. Study sites. Participants will be recruited from the following hospital sites: Blacktown Hospital Westmead Hospital Research sites involved in sample analysis: Westmead Institute for Medical Research Blacktown Clinical School and Research Centre Patient data collection. Baseline clinicopathological information will be collected from enrolled participants using electronic medical record data available at CERNER and ARIA hospital databases. Sample collection. The following specimens will be collected from all participants at baseline: Peripheral blood (3 x 10mL EDTA tubes) FibroScan (optional) Formalin-Fixed Paraffin-Embedded (FFPE) samples (one block) from core biopsies which is a part of routine care for cancer patients if available. The following specimens will be collected after ICI-based therapeutic regimens will be commenced (week 6-9 after ICI-therapy commencement): • Peripheral blood (3 x 10mL EDTA tubes) Upon confirmation of irAEs, the following samples will be collected: Peripheral blood (3 x 10mL EDTA tubes) FibroScan (for patients with hepatic irAEs) Tissue samples if available (for patients with immune-mediated colitis who will be required to undergo routine colonoscopy by their treating oncologist) Peripheral blood samples from patients will be collected using 10ml EDTA vacutainer tubes (x3) and processed within 12 hours of collection by research staff at each site. Blood samples will be centrifuged at 800g for 15 minutes for plasma collection. Plasma will be stored at -80oC until enzyme linked immunosorbent analysis (ELISA) will be performed. PBMCs will be collected using Ficoll gradient within 12 hours of collection on site and stored at -80oC. PBMCs will be used for flow cytometry phenotyping of T cells. Total RNA from PBMCs will be extracted and stored at -80oC until further next generation sequencing analysis. Consent to the study will allow researchers to access the baseline diagnostic FFPE samples for assessment of tumour ncRNA/mRNA profiling. Tissue samples obtained from patients with severe immune-mediated colitis during the routine colonoscopy will be processed in order to obtain total RNA and immune cells, which will be then frozen at -80oC until further NGS and flow cytometry assays.

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