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

NCT ID: NCT04807127

Last Updated: 2024-07-01

Basic Information

• Recruitment Status: RECRUITING
• Total Enrollment: 60 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2020-02-01
• Study Completion Date: 2025-01-31

Brief 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.

Detailed 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.

Conditions

Pneumonitis, Interstitial; Immunotherapy; Immune-related Adverse Events

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Study Groups

ICI-pneumonitis

Cancer patients experiencing ICI-pneumonitis

Immune checkpoint blockade

Intervention Type: DRUG

ICI, administered as standard-of-care treatment

Radiotherapy induced pneumonitis

Cancer patients experiencing RT-pneumonitis

Radiotherapy

Intervention Type: RADIATION

RT, administered as standard-of-care treatment

TKI-induced pneumonitis

Cancer patients experiencing TKI-induced pneumonitis

Targeted therapy

Intervention Type: DRUG

TKI, administered as standard-of-care treatment

Interventions

Immune checkpoint blockade

ICI, administered as standard-of-care treatment

Intervention Type: DRUG

Targeted therapy

TKI, administered as standard-of-care treatment

Intervention Type: DRUG

Radiotherapy

RT, administered as standard-of-care treatment

Intervention Type: RADIATION

Other Intervention Names

Pembrolizumab; Durvalumab; TKI

Eligibility Criteria

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-induced pneumonitis
• Not included in other clinical trials
• Signed informed consent form

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 120 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

KU Leuven

OTHER

Sponsor Role: collaborator

Universitaire Ziekenhuizen KU Leuven

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Els Wauters, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

University Hospitals - KU Leuven

Locations

Universitaire Ziekenhuizen Leuven

Leuven, Flemish Brabant, Belgium

Site Status: RECRUITING

Countries

Belgium

Central Contacts

Els Wauters, MD, PhD

Role: CONTACT

els.wauters@uzleuven.be

+3216340942

Facility Contacts

Els Wauters, MD, PhD

Role: primary

els.wauters@uzleuven.be

016340942

Other Identifiers

S63357

Identifier Type: -

Identifier Source: org_study_id