Lung Diseases, InterstitialNCT04807114
A Single-cell Approach to Identify Biomarkers of Efficacy and Toxicity for ICI in NSCLC
An observational study of Lung Diseases, Interstitial and NSCLC, run by Universitaire Ziekenhuizen KU Leuven at 1 site in Belgium.
Trial summary
The main goal of this prospective non-interventional exploratory study is to characterize the tumor micro-environment of advanced NSCLC in single-cell resolution, prior to immune checkpoint blockade exposure, and correlate the findings to clinical outcome. Read more about this study
- Who is it for?
- Ages 18 to 120 years
- Conditions the study is for
- Lung Diseases, Interstitial, NSCLC, Immunotherapy
- What is being tested?
- Immune checkpoint inhibitor and Chemotherapy + Immune checkpoint inhibitor
- Type of treatment
- Injection or infusion
- How many people
- 70 participants
- Where
- 1 siteBelgium
- Study dates
- 1 Feb 2020to 31 Jan 2025
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 120 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: Patients treated with first-line anti-PD-1 Pembrolizumab (+- chemotherapy) for stage IV non-small cell lung cancer
Who may be able to join
- Adult M/F/X (>= 18 years)
- Histologically and clinically confirmed diagnosis of non-small cell lung cancer (according to IASLC Staging Handbook in Thoracic Oncology v7)
- Patients receiving first-line treatment per guidelines
- Not included in other clinical trials
- Signed informed consent form
Who cannot join
- 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 locations and contacts
1 site in 1 country.
Belgium1 site, 1 recruiting
- Recruiting
Universitaire Ziekenhuizen Leuven
Leuven, 3000
Els Wauters, MD, PhD, +32 16 34 09 42, els.wauters@uzleuven.be
About this study
Official title: A Single-cell Approach to Identify Biomarkers of Efficacy and Toxicity for Immune Checkpoint Blockade in Non-small Cell Lung Cancer
The main goal of this prospective non-interventional exploratory study is to characterize the tumor micro-environment of advanced NSCLC in single-cell resolution, prior to immune checkpoint blockade exposure, and correlate the findings to clinical outcome. This approach will allow to generate new hypotheses regarding mechanism of action of ICI and (primary) resistance mechanisms. The long-term goal is that these novel mechanistic insights will be translated to a clinical setting to develop better biomarkers of ICI efficacy. Importantly, since the investigators will also sequentially profile the immune composition of peripheral blood, this research offers an opportunity to develop circulating (non-invasive) biomarkers.
A second aim is to characterize the immune cell composition of bronchoalveolar lavage (BAL) fluid from these ICI-treated cancer patients if they would develop ICI-pneumonitis. These mechanistic insights can directly lead to putative diagnostic biomarkers and therpeutic targets. Since single-cell profiling of blood samples will also be performed, circulating biomarkers of ICI toxicity can also be identified, making non-invasive diagnosis feasible.
Read the detailed description
The investigators will collect tumor biopsies from 70 st.IV NSCLC patients before start of treatment with immune checkpoint inhibitors. These biopsies are taken during a medically required routine procedure for diagnostic purposes, and will be subjected to the following experimental procedures:
First, scRNA-seq and TCR-seq will be applied on up to 5,000 randomly dissociated cells. 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 enable the researchers 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 (non-exhaustive):
- 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, including fibroblasts and endothelial cells.
- 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 sub-clusters 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. Since high CD8+ T cell activity correlates with high immune checkpoint expression, T cell activity (based on granzyme expression) will be correlated with expression of other genes in these cells to identify co-regulated receptors, which possibly represent novel checkpoint molecules.
Blood samples will be subjected to similar experimental procedures. First, 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 tumor biopsies.
As a second objective, immune profiling of the cellular composition of ICI-pneumonitis BAL fluid and PBMC will be performed using scRNA-seq, scTCR-seq and CITE-seq as previously outlined.
- Conditions
- Lung Diseases, Interstitial, NSCLC, Immunotherapy
- Being tested
- Immune checkpoint inhibitor, Chemotherapy + Immune checkpoint inhibitor
- Medical subject headings
- Lung Diseases, Interstitial
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Immune checkpoint inhibitorDrug
Also called Pembrolizumab
Standard-of-care treatment for st.IV NSCLC (no driver mutation, PD-L1 > 50%)
Chemotherapy + Immune checkpoint inhibitorDrug
Also called Pembrolizumab
Standard-of-care treatment for st.IV NSCLC (no driver mutation, PD-L1 < 50%)
| Study group | Role | What they receive |
|---|---|---|
| NSCLC st.IV (PD-L1 > 50%) | Anti-PD-1 monotherapy Receives: Drug: Immune checkpoint inhibitor | |
| NSCLC st.IV (PD-L1 < 50%) | Combination anti-PD-1 + chemotherapy Receives: Drug: Chemotherapy + Immune checkpoint inhibitor |
What is being measured
The primary outcome is the main question the study is designed to answer.
Immune cell proportions, as determined by scRNA-seq, present in tumor samples of ICI-treated st.IV NSCLC patients attaining objective response or not attaining objective response
By identifying and statistically comparing the percentages of immune cell subtypes present in responding vs. non-responding patients' tumors before start of ICI therapy, we aim to i) understand which immune processes drive response or resistance to ICI ii) identify putative molecular biomarkers iii) identify putative therapeutic targets
Measured: From date of inclusion until study completion, on average 2 years.
Immune cell proportions, as determined by scRNA-seq, present in peripheral blood of ICI-treated st.IV NSCLC patients attaining objective response or not attaining objective response, before and after 1 cycle of ICI
By identifying and statistically comparing the percentages of immune cell subtypes present in responding vs. non-responding patients' peripheral blood, we aim to i) understand which immune processes drive response or resistance to ICI ii) identify putative molecular biomarkers iii) identify putative therapeutic targets
Measured: From date of inclusion until study completion, on average 2 years.
Secondary outcomes (2)
Immune cell proportions, as determined by scRNA-seq, present in ICI-induced pneumonitis BAL fluid
By identifying and statistically comparing the percentages of immune cell subtypes present in ICI-/RT-/TKI-induced pneumonitis BAL fluid, we aim to i) understand which immune processes drive these adverse events ii) identify putative molecular biomarkers iii) identify putative therapeutic targets
Measured: From date of inclusion until study completion, on average 2 years.
Immune cell proportions, as determined by scRNA-seq, present in ICI-induced pneumonitis peripheral blood mononuclear cells
By identifying and statistically comparing the percentages of immune cell subtypes present in ICI-/RT-/TKI-induced pneumonitis peripheral blood mononuclear cells, we aim to i) understand which immune processes drive these adverse events ii) identify putative molecular biomarkers iii) identify putative therapeutic targets
Measured: From date of inclusion until study completion, on average 2 years.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Mar 2021
- Study start1 Feb 2020
- Primary completion31 Jan 2025 (estimated)
- Study completion31 Jan 2025 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Lung Diseases, InterstitialStudies of the same condition, open and under way.
- More trials run by Universitaire Ziekenhuizen KU LeuvenThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 70 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Universitaire Ziekenhuizen KU Leuven
- Sponsor type
- University, hospital or other
- Collaborators
- KU Leuven
- Responsible party
- Sponsor
- Investigators
- Els Wauters, MD, PhD, Principal investigator, University Hospitals - KU Leuven
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04807114
- Sponsor's protocol ID
- S63531
- Status last verified
- Jun 2024
- First submitted
- 10 Mar 2021
- Last updated
- 1 Jul 2024
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 1 Jul 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Single-cell Approach to Identify Biomarkers of Efficacy and Toxicity for Immune Checkpoint Blockade in Non-small Cell Lung Cancer
- ClinicalTrials.gov ID
- NCT04807114
- Acronym / sponsor ID
- S63531
- Conditions
- Lung Diseases, Interstitial, NSCLC, Immunotherapy
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 70 participants (estimated)
- Lead sponsor
- Universitaire Ziekenhuizen KU LeuvenUniversity, hospital or other
- Collaborators
- KU Leuven
- Study start
- 1 Feb 2020 (actual)
- Primary completion
- 31 Jan 2025 (estimated)
- Study completion
- 31 Jan 2025 (estimated)
- First posted
- 19 Mar 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The main goal of this prospective non-interventional exploratory study is to characterize the tumor micro-environment of advanced NSCLC in single-cell resolution, prior to immune checkpoint blockade exposure, and correlate the findings to clinical outcome. This approach will allow to generate new hypotheses regarding mechanism of action of ICI and (primary) resistance mechanisms. The long-term goal is that these novel mechanistic insights will be translated to a clinical setting to develop better biomarkers of ICI efficacy. Importantly, since the investigators will also sequentially profile the immune composition of peripheral blood, this research offers an opportunity to develop circulating (non-invasive) biomarkers.
A second aim is to characterize the immune cell composition of bronchoalveolar lavage (BAL) fluid from these ICI-treated cancer patients if they would develop ICI-pneumonitis. These mechanistic insights can directly lead to putative diagnostic biomarkers and therpeutic targets. Since single-cell profiling of blood samples will also be performed, circulating biomarkers of ICI toxicity can also be identified, making non-invasive diagnosis feasible.
Detailed description
The investigators will collect tumor biopsies from 70 st.IV NSCLC patients before start of treatment with immune checkpoint inhibitors. These biopsies are taken during a medically required routine procedure for diagnostic purposes, and will be subjected to the following experimental procedures:
First, scRNA-seq and TCR-seq will be applied on up to 5,000 randomly dissociated cells. 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 enable the researchers 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 (non-exhaustive):
- 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, including fibroblasts and endothelial cells.
- 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 sub-clusters 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. Since high CD8+ T cell activity correlates with high immune checkpoint expression, T cell activity (based on granzyme expression) will be correlated with expression of other genes in these cells to identify co-regulated receptors, which possibly represent novel checkpoint molecules.
Blood samples will be subjected to similar experimental procedures. First, 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 tumor biopsies.
As a second objective, immune profiling of the cellular composition of ICI-pneumonitis BAL fluid and PBMC will be performed using scRNA-seq, scTCR-seq and CITE-seq as previously outlined.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| NSCLC st.IV (PD-L1 > 50%) | – | Drug: Immune checkpoint inhibitorAnti-PD-1 monotherapy |
| NSCLC st.IV (PD-L1 < 50%) | – | Drug: Chemotherapy + Immune checkpoint inhibitorCombination anti-PD-1 + chemotherapy |
Who may qualify
- Ages
- 18 to 120 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- Patients treated with first-line anti-PD-1 Pembrolizumab (+- chemotherapy) for stage IV non-small cell lung cancer
Key inclusion criteria (5 listed)
- Adult M/F/X (>= 18 years)
- Histologically and clinically confirmed diagnosis of non-small cell lung cancer (according to IASLC Staging Handbook in Thoracic Oncology v7)
- Patients receiving first-line treatment per guidelines
- Not included in other clinical trials
- Signed informed consent form
Key exclusion criteria (1 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Immune checkpoint inhibitorAlso: PembrolizumabStandard-of-care treatment for st.IV NSCLC (no driver mutation, PD-L1 > 50%) | Drug | NSCLC st.IV (PD-L1 > 50%) |
| Chemotherapy + Immune checkpoint inhibitorAlso: PembrolizumabStandard-of-care treatment for st.IV NSCLC (no driver mutation, PD-L1 < 50%) | Drug | NSCLC st.IV (PD-L1 < 50%) |
Primary outcome
Immune cell proportions, as determined by scRNA-seq, present in tumor samples of ICI-treated st.IV NSCLC patients attaining objective response or not attaining objective response
Time frame: From date of inclusion until study completion, on average 2 years.
By identifying and statistically comparing the percentages of immune cell subtypes present in responding vs. non-responding patients' tumors before start of ICI therapy, we aim to i) understand which immune processes drive response or resistance to ICI ii) identify putative molecular biomarkers iii) identify putative therapeutic targets
Immune cell proportions, as determined by scRNA-seq, present in peripheral blood of ICI-treated st.IV NSCLC patients attaining objective response or not attaining objective response, before and after 1 cycle of ICI
Time frame: From date of inclusion until study completion, on average 2 years.
By identifying and statistically comparing the percentages of immune cell subtypes present in responding vs. non-responding patients' peripheral blood, we aim to i) understand which immune processes drive response or resistance to ICI ii) identify putative molecular biomarkers iii) identify putative therapeutic targets
2 secondary outcomes
Immune cell proportions, as determined by scRNA-seq, present in ICI-induced pneumonitis BAL fluid
Time frame: From date of inclusion until study completion, on average 2 years.
Immune cell proportions, as determined by scRNA-seq, present in ICI-induced pneumonitis peripheral blood mononuclear cells
Time frame: From date of inclusion until study completion, on average 2 years.
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Jul 2024.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Els Wauters, MD, PhD principal investigator
University Hospitals - KU Leuven
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Lung Diseases, Interstitial and NSCLC, run by Universitaire Ziekenhuizen KU Leuven at 1 site in Belgium.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 1 Jul 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Belgium. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Els Wauters (+3216340942, els.wauters@uzleuven.be), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Immune cell proportions, as determined by scRNA-seq, present in tumor samples of ICI-treated st.IV NSCLC patients attaining objective response or not attaining objective response (time frame: From date of inclusion until study completion, on average 2 years.). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Jul 2024.