Myeloid Cell Reprogramming in Thyroid Carcinoma

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

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.

Study Overview

• Status: Completed
• Conditions: 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:

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 factors 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 Type: Observational
• Enrollment (Actual): 41

Contacts and Locations

Study Locations

• Netherlands
  • Nijmegen, Netherlands, 6525GA
    • Radboudumc

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Primary care clinic

Description

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

Study Plan

How is the study designed?

Number of groups / cohorts

5

Cohorts and Interventions

Group / Cohort
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Transcriptional reprogramming of myeloid cells	RNAseq	baseline
Epigenetic reprogramming of myeloid cells	ATAC-seq	baseline
Functional reprogramming of myeloid cells	Cytokine response	baseline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Metabolites	Presence and level metabolites	baseline
Change of reprogramming after RAI treatment	RNAseq	baseline and 7 days after RAI treatment

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Investigators: Principal Investigator: Romana T Netea-Maier, Endocrinologist

Study record dates

Study Major Dates

• Study Start (Actual): March 6, 2018
• Primary Completion (Actual): November 26, 2019
• Study Completion (Actual): January 5, 2021

Study Registration Dates

• First Submitted: December 18, 2017
• First Submitted That Met QC Criteria: January 5, 2018
• First Posted (Actual): January 11, 2018

Study Record Updates

• Last Update Posted (Actual): February 9, 2022
• Last Update Submitted That Met QC Criteria: January 25, 2022
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Keywords: monocyte; myeloid cell; reprogramming; tumor-associated macrophage
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Site; Endocrine System Diseases; Endocrine Gland Neoplasms; Head and Neck Neoplasms; Thyroid Diseases; Thyroid Neoplasms
• Other Study ID Numbers: NL62671.091.17; 2017-3628 (Other Identifier: CMO Arnhem-Nijmegen)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No