Myeloid Cell Reprogramming in Thyroid Carcinoma

Sponsor

Radboud University Medical Center (Other)

Overall Status

Completed

CT.gov ID

NCT03397238

Collaborator

(none)

Enrollment

Location

Actual Duration (Months)

1.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study investigates the reprogramming of myeloid cells in patients with thyroid carcinoma. The investigators hypothesize that tumor-derived factors change the function of myeloid cells (peripheral blood and bone marrow-derived) in such a way that these immune cells promote tumor growth rather than combat the tumor.

Condition or Disease	Intervention/Treatment	Phase
Thyroid Cancer

Detailed Description

Description of the problem:

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.

Envisioned solution/research direction:

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:

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 factors even before their recruitment in the TME.
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 Design

Study Type:

Observational

Actual Enrollment :

41 participants

Observational Model:

Case-Control

Time Perspective:

Prospective

Official Title:

Myeloid Cell Reprogramming in the Context of Radioiodine Therapy in Patients With Non-Medullary Thyroid Carcinoma

Actual Study Start Date :

Mar 6, 2018

Actual Primary Completion Date :

Nov 26, 2019

Actual Study Completion Date :

Jan 5, 2021

Arms and Interventions

Arm	Intervention/Treatment
Non-metastatic TC blood withdrawal, bone marrow aspiration
Metastatic TC blood withdrawal, bone marrow aspiration
MNG surgery blood withdrawal, bone marrow aspiration
MNG RAI treatment blood withdrawal
Healthy volunteers blood withdrawal

Outcome Measures

Primary Outcome Measures

Transcriptional reprogramming of myeloid cells [baseline]
RNAseq
Epigenetic reprogramming of myeloid cells [baseline]
ATAC-seq
Functional reprogramming of myeloid cells [baseline]
Cytokine response

Secondary Outcome Measures

Metabolites [baseline]
Presence and level metabolites
Change of reprogramming after RAI treatment [baseline and 7 days after RAI treatment]
RNAseq

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Group 1:

Subject is newly diagnosed with TC, therapy-naive and is planned to receive conventional treatment by surgery followed by RAI; no evidence of local or distant metastases

Group 2:

Subject has TC with evidence of distant metastases (either newly diagnosed or therapy-naive or patients with persistent or recurrent disease); at least 4 months since the previous treatment with RAI if applicable

Group 3:

Subject is diagnosed with MNG, is euthyroid, and is planned to undergo surgery - Group 4:

Subject is diagnosed with MNG, is euthyroid, and is planned to receive RAI treatment

Group 5: Healthy individuals who are euthyroid and have no evidence of thyroid disease

Exclusion Criteria:

Mentally incompetent
Pregnant, trying to become pregnant or breastfeeding
Known inflammatory or infectious diseases or an immunosuppressive status
Using medication interfering with the immune system
Reduced platelet 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