A Single-cell Approach to Identify Biomarkers of Pulmonary Toxicity for Immune Checkpoint Blockade

Last updated: June 28, 2024
Sponsor: Universitaire Ziekenhuizen KU Leuven
Overall Status: Active - Recruiting

Phase

N/A

Condition

Pneumonia

Vaccines

Cancer

Treatment

Targeted therapy

Immune checkpoint blockade

Radiotherapy

Clinical Study ID

NCT04807127
S63357
  • Ages 18-120
  • All Genders

Study Summary

The main goal of this prospective non-interventional exploratory monocentric study is to characterize the immune cell composition of bronchoalveolar lavage (BAL) fluid from cancer patients experiencing cancer therapy-induced pneumonitis on a single-cell scale. These mechanistic insights can directly lead to putative diagnostic biomarkers and therapeutic targets.

A second highly clinically relevant hypothesis is that single-cell profiling of blood samples will reveal circulating biomarkers of ICB toxicity, making non-invasive diagnosis feasible.

Eligibility Criteria

Inclusion

Inclusion criteria:

  • Adult M/F/X (>= 18 years)

  • Patients receiving or having received treatment per guidelines

  • Patients undergoing bronchoscopy with BAL, for possible cancer treatment-inducedpneumonitis

  • Not included in other clinical trials

  • Signed informed consent form

Exclusion

Exclusion criteria:

• Collected material not suitable for further processing in this study (e.g. bad quality). This decision will be made in consultation with a lab technician and/or bio-informatician, specialized in single-cell analysis.

Study Design

Total Participants: 60
Treatment Group(s): 3
Primary Treatment: Targeted therapy
Phase:
Study Start date:
February 01, 2020
Estimated Completion Date:
January 31, 2025

Study Description

The investigators will apply single cell RNA- and TCR-sequencing on up to 5,000 single cells per sample. Additionally, cell surface protein expression can be integrated with the transcriptional information. Various bioinformatics pipelines, including Seurat, will be used to identify different cell clusters, which through marker gene expression will be assigned to known cell types, cellular subtypes or phenotypes. For instance, this will make it possible to monitor the abundance of PD-1/PD-L1 expressing T-cells, cytotoxic T-cells, immune-suppressive myeloid cells etc. The following parameters at single-cell level will be relevant, amongst others:

  • The composition and relative abundancies of established immune cell types (e.g. T cells (CD4+, CD8+ and regulatory subsets), NK cells, B cells, MDSCs, macrophages, neutrophils, dendritic cells). Transcriptomic data for each of these immune cell subtypes will be analyzed, allowing characterization of specific gene expression programs that define specific phenotypic states.

  • Composition of all stromal cellular subtypes identified by single-cell transcriptomics.

  • A gene regulatory network for each cell type and cellular subtype (or cell state) will be established and master transcriptional regulators will be identified. Individual T-cells and T-cell subclusters will be classified based on interferon activation, high rates of proliferation and transcription and increased granzyme expression, which are all indicative of T-cell activation.

Blood samples will be subjected to similar single-cell experimental procedures. First, peripheral blood mononuclear cells (PBMC) are isolated using Ficoll density gradient centrifugation. Single-cell transcriptome analysis in combination with CITE-seq will be performed on 5000 PBMC. Cellular composition will be determined using the same bioinformatic pipelines as used for processing the BAL fluid cells.

Connect with a study center

  • Universitaire Ziekenhuizen Leuven

    Leuven, Flemish Brabant 3000
    Belgium

    Active - Recruiting

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