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

Study Purpose

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.

Recruitment Criteria

Accepts Healthy Volunteers Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms	No
Study Type An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes. An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes. Searching Both is inclusive of interventional and observational studies.	Observational
Eligible Ages	18 Years and Over
Gender	All

More Inclusion & Exclusion 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.

Trial Details

Trial ID: This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.	NCT04807127
Phase Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans. Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data. Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.
Lead Sponsor The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.	Universitaire Ziekenhuizen KU Leuven
Principal Investigator The person who is responsible for the scientific and technical direction of the entire clinical study.	Els Wauters, MD, PhD
Principal Investigator Affiliation	University Hospitals - KU Leuven
Agency Class Category of organization(s) involved as sponsor (and collaborator) supporting the trial.	Other
Overall Status	Recruiting
Countries	Belgium
Conditions The disease, disorder, syndrome, illness, or injury that is being studied.	Pneumonitis, Interstitial, Immunotherapy, Immune-related Adverse Events

Additional Details

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.

Arms & Interventions

Arms

: ICI-pneumonitis

Cancer patients experiencing ICI-pneumonitis

: Radiotherapy induced pneumonitis

Cancer patients experiencing RT-pneumonitis

: TKI-induced pneumonitis

Cancer patients experiencing TKI-induced pneumonitis

Interventions

Drug: - Immune checkpoint blockade

ICI, administered as standard-of-care treatment

Drug: - Targeted therapy

TKI, administered as standard-of-care treatment

Radiation: - Radiotherapy

RT, administered as standard-of-care treatment

Contact a Trial Team

If you are interested in learning more about this trial, find the trial site nearest to your location and contact the site coordinator via email or phone. We also strongly recommend that you consult with your healthcare provider about the trials that may interest you and refer to our terms of service below.