Primary Objective: To assess the transcriptional, epigenetic and functional reprogramming of TAMs, circulating monocytes and BM myeloid progenitors cells in active and advanced metastatic TC and to assess the effect of RAI treatment on the…
ID
Source
Brief title
Condition
- Endocrine neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Transcriptional and epigenetic signature and function of TAMs, BM myeloid
progenitors and circulating macrophages before and after treatment.
Secondary outcome
Presence of circulating tumor cells (CTC) and changes in circulating
metabolites (either tumor-derived or tumor-induced) concentrations
(metabolomics) associated with the functional reprograming of the immune cells.
Background summary
Non-medullary thyroid carcinoma (TC) is the most common endocrine malignancy
and its incidence is one of the most rapidly increasing among the cancer types.
For many patients with advanced and poorly differentiated tumors, treatment
options are limited and the prognosis of advanced stage metastatic disease
remains poor.
To improve the patients outcome and identify novel therapeutic targets, one
needs a *systems understanding* of the pathophysiology of tumors, particularly
the complex interaction of the malignant cells with other cell types in the
tumor en the tumor environment (TME), especially immune cells. Tumor-associated
macrophages (TAMs), the most dominant myeloid population in aggressive thyroid
tumors, exhibit a distorted phenotype functioning predominantly as tumor
enhancer. Despite the progress in understanding the importance of TAMs, the
in-depth characterization of different TAMs populations is lacking and the
mechanisms governing the functional polarization of TAMs are largely unknown.
Understanding the interplay between TAMs and tumor cells represents a crucial
step towards development of additional therapeutic strategies in cancer.
Hypothesis:
1. We first propose that in advanced TC, not only TAMs, but also circulating
monocytes and bone marrow (BM) myeloid progenitors are functionally
reprogrammed by tumor-derived metabolites even before their recruitment in the
TME.
2. Radioactive iodide (I131)(RAI) is a very effective therapy for patients with
TC, but is less effective in patients with advanced, metastatic tumors. We
hypothesize that by exposing tumor antigens to the immune system, RAI might
induce immunogenic effects at the level of the TME with reprogramming of both
TAMs present in the TME and circulating monocytes, towards a tumor suppressive
phenotype. This may further potentiate the effects of RAI. In addition this
could be explored in the future as a basis for immunotherapy for tumors that
are refractory to conventional treatment.
Study objective
Primary Objective:
To assess the transcriptional, epigenetic and functional reprogramming of TAMs,
circulating monocytes and BM myeloid progenitors cells in active and advanced
metastatic TC and to assess the effect of RAI treatment on the reprogramming of
circulating monocytes.
Secondary Objectives:
To investigate whether the presence of circulating tumor cells (CTC) and
changes in circulating metabolites (either tumor-derived or tumor-induced)
concentrations (metabolomics) are associated with the functional reprograming
of the immune cells.
Study design
investigator initiated, single-center explorative cross-sectional study at the
Radboudumc Nijmegen
Study burden and risks
There are no risks associated with the study. There are no interventions other
than those related to the regular patient care except for a BM aspiration that
will take place during surgery. The burden for the patients will be maintained
to a minimum. They will only be required to donate a limited number of blood
samples (2-4 times for the patients and once for the healthy volunteers) and
small samples of their removed thyroid tissue in case of surgery. To minimize
the discomfort, BM samples will be collected during the same surgery under
general anesthesia. For the same reason we have chosen not to collect BM from
our healthy controls.
Geert Grooteplein 8
Nijmegen 6525 GA
NL
Geert Grooteplein 8
Nijmegen 6525 GA
NL
Listed location countries
Age
Inclusion criteria
Group 1:
-newly diagnosed patients with TC that are therapy naïve and are planned to
receive conventional treatment by surgery followed by RAI.
-no evidence of local or distant metastases
Group 2:
-patients with TC with evidence of distant metastases (either newly diagnosed
patients who are therapy naïve or patients with persistent or recurrent
disease) and are planned to receive conventional treatment by surgery followed
by RAI.
-at least 4 months since the previous treatment with RAI (in the patients who
have had this treatment in the past)
Group 3:
-patients with MNG in which the decision has been taken to undergo surgery
because of obstructive symptoms or for cosmetic reasons
Group 4:
-patients with MNG in which the decision has been taken to undergo RAI because
of obstructive symptoms.
Group 5:
-healthy individuals without evidence of thyroid disease.
Exclusion criteria
Excluded from participation in this study will be subjects who are/have:
Mentally incompetent;
Pregnant or breastfeeding;
Known inflammatory or infectious diseases or an immunosuppressive status;
Using medication interfering with the immune system;
Reduced platelets counts or other conditions associated with an increased risk
of bleeding.
Severe comorbidities: other active malignancy (except for basal cell
carcinoma), serious psychiatric pathology;
A self-reported alcohol consumption of >21 units per week.
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 | NL62671.091.17 |