Abstract 775P
Background
Immune checkpoint inhibitors (ICIs) improve the survival of patients with urothelial cancer (UC). However, objective responses are observed in only 20% of patients. Predictive biomarkers that identify patients who benefit from ICIs are urgently needed. Additionally, a better understanding of the molecular and cellular events that mediate response to ICIs, might improve our understanding of response heterogeneity and provide targets for new combination strategies.
Methods
Whole blood samples from 31 patients with metastatic UC were collected before and after 2-6 weeks of anti-PD-1 therapy. Clinical benefit was defined as progression-free survival ≥ 6 months. Eighteen patients were classified as non-progressive (non-PD) and 13 as progressive (PD) patients. Transcriptome profiles of these samples as well as samples from 10 healthy donors were generated by RNA sequencing with globin and rRNA depletion.
Results
Differential Expression Analysis (DEA) between non-PD and PD at baseline identified 351 differentially expressed genes (DEGs) (padj<0.01 and a |FC|>2), all downregulated in non-PD. Interestingly, functional analysis highlighted a clear downregulated cluster of 44 genes related to extracellular matrix (ECM) and cell adhesion. The great majority of DEGs (n=293) were not expressed in blood from healthy donors, including 39 DEGs of the ECM cluster. We hypothesize that these ECM RNAs derived from the tumor and present in whole blood as cell-free or exosomal RNA. When comparing baseline and on-treatment samples, we detected 51 DEGs in non-PD and no DEGs in PD (padj <0.05). In non-PD, expression of most DEGs increased during therapy (37/51). Among the DEGs were multiple genes involved in cell cycle/DNA replication. In complete responders, also an upregulation of interferon signaling genes was observed during the first weeks of treatment.
Conclusions
Whole blood transcriptome profiling is a promising tool to identify UC patients who benefit from ICIs and to understand biological processes underlying response. Future plans include verifying whether the detected ECM genes are expressed in exosomes and tumor tissue of these patients and expanding the current cohort.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
L. Ciarloni: Shareholder/Stockholder/Stock options, Full/Part-time employment: Novigenix SA. S. Hosseinian Ehrensberger: Shareholder/Stockholder/Stock options, Full/Part-time employment: Novigenix SA. V. Wosika: Full/Part-time employment: Novigenix SA. N. Mehra: Advisory/Consultancy, Research grant/Funding (institution): Roche; Advisory/Consultancy, Travel/Accommodation/Expenses: MSD; Advisory/Consultancy: BMS; Advisory/Consultancy: Bayer; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Astellas; Advisory/Consultancy, Research grant/Funding (institution): Janssen; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Sanofi Genzyme. All other authors have declared no conflicts of interest.