The purpose of this project is to provide a rational basis for the selection of small-molecule inhibitors that block the signalling of all cytokines involved in type I enteropathy-associated T cell lymphoma (type I EATL).
ID
Source
Brief title
Condition
- Lymphomas non-Hodgkin's T-cell
- Malabsorption conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
It is currently unclear how the signalling pathways set off by TNF, IL-2 and
IL-21 synergize to promote lymphoma growth. This project*s first goal is
therefore to identify key signalling pathways activated by these cytokines and
small-molecule inhibitors targeting these pathways. The efficacy of such
inhibitors will be tested ex vivo using patient biopsies. This will allow a
rational selection of drugs for future clinical trials, in which the predictive
value of this ex vivo assay will also be evaluated.
Secondary outcome
Single-cell CyTOF:
1. Explore heterogeneity of the immune system between RCDII patients
2. Track the transition of the immune system in patients with celiac disease to
patients with RCDII.
Imaging CyTOF:
1. Validation of interesting immune cell subsets identified in single cell CyTOF
2. Look at immune cell composition in patients with CeD/RCDII.
Single-cell RNA sequencing:
1. Explore heterogeneity of gene expression between patients with RCDII.
FACS (sort), culture, cytotoxicity assays:
1. Functionality assays on immune cell subsets found to be specific for
CeD/RCDII.
Background summary
Although the survival rates for most lymphomas have improved considerably over
the past decades, mature T cell and NK cell lymphomas remain notoriously
difficult to treat. One such lymphoma is type I enteropathy-associated T cell
lymphoma (type I EATL), a malignant expansion of duodenal intraepithelial
lymphocytes (IEL) with a 5-year survival rate below 20%. These malignant cells
are already found expanded in premalignant stages of EATL. The inflammatory
cytokine interleukin-15 (IL-15) promotes the survival and proliferation of
malignant cells. This cytokine and associated signalling pathways are therefore
currently considered the most promising targets for novel therapies. However,
our preliminary results show that additional cytokines (TNF, IL-2, IL-21),
produced by inflammatory CD4+ T cells involved in the development of pre-EATL,
together have the ability to make an equally large contribution to lymphoma
growth, through signalling pathways that are incompletely understood.
Study objective
The purpose of this project is to provide a rational basis for the selection of
small-molecule inhibitors that block the signalling of all cytokines involved
in type I enteropathy-associated T cell lymphoma (type I EATL).
Study design
Fundamental research.
Study burden and risks
There is no additional burden for the patient. Patients undergo conscious
sedation. Additional procedure time is less than 5 minutes. The risk of taking
extra biopsies during a planned endoscopy is negligible. Taking biopsies during
endoscopy can cause intra-intestinal or intramural haemorrhage, or perforation.
The risk is estimated to be < 1 : 10000 for a diagnostic
oesophago-gastroduodenoscopy. The risk (of infection) of taking 4mL blood out
of an existing i.v. is also negligible.
Boelelaan 1118
Amsterdam 1081 HZ
NL
Boelelaan 1118
Amsterdam 1081 HZ
NL
Listed location countries
Age
Inclusion criteria
- * 18 years old
- Indication for a biopsy for the diagnosis or monitoring of:
non-CD / non-inflamed, CD / non-inflamed, active CD, pre-EATL, EATL
- Given informed consent
Exclusion criteria
- No informed consent
- Insufficient knowledge of Dutch language and/or inability to understand the
information provided.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL60645.029.17 |