Hereditary Pheochromocytoma Assessment of Tumour Immunologies (HEPHESTOS)

HEPHESTOS - Hereditary Pheochromocytoma Assessment of Tumour Immunologies

In this study, the investigators are examining the role of the immune system in pheochromocytoma and paraganglioma. The investigators aim to examine the differences in the immune system between people who have these tumors with and without a hereditary predisposition. The investigators also want to see how the immune system changes during the development of the tumor in people with a hereditary predisposition. Finally, the investigators will compare the data with a control group of people without these tumors. Ultimately, the investigators hope that the results will contribute to the discovery of new immune system-targeted medications for pheochromocytoma and paraganglioma.

Study Overview

• Status: Recruiting
• Conditions: Pheochromocytoma; Paraganglioma
• Intervention / Treatment: Procedure: Venepuncture; Procedure: Venepuncture

Detailed Description

Rationale: Pheochromocytoma and Paraganglioma (PPGL) represent rare, catecholamine-secreting tumours (1). Genetic or sporadic mutations, accounting for approximately 70% of cases, significantly contribute to PPGL development, and are categorized into three clusters based on tumour formation mechanisms (2,3). Current treatment options, particularly for advanced or metastatic disease, are limited (4). Understanding the immune system's role and the impact of genetics on tumour immunology in PPGL could unveil crucial insights for therapeutic advancements. Earlier studies emphasized the immunogenic nature of PPGL, highlighting the tumour microenvironment (TME) and circulatory factors as key components (5-7). However, these studies lack specific examination of genotypes' effect on the immune system. This study aims to address this gap in two parts, particularly focusing on differences between genetic clusters.

Objective: To examine the differences in the immune system in PPGL regarding genetics. Part I will examine immune cell composition and response in circulation. Part II will examine immune cell composition in TME.

Study design: Part I will be a partly cross-sectional and partly prospective cohort study. Part II will be a histological study of retrospectively and prospectively collected PPGL samples.

Study population: Part I will include 80 patients with PPGL, 80 carriers of germline mutations predisposing for PPGL, and 40 sex and age matched healthy volunteers. Part II will include histological samples of 80 patients with hereditary disease and 80 patients with sporadic disease.

Main study parameters/endpoints: The main study outcomes are inflammatory molecules and proteins produced by stimulated and unstimulated immune cells from circulation, immune cell composition in histological PPGL samples and in circulation, and their genetic determinants. Secondary outcomes will comprise of transcriptional and epigenetic signature of circulating immune cells, circulating immunomodulating metabolites, trained immunity, and clinical outcomes such as tumour metastasis, survival.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: For patients and mutation carriers, there is no direct benefit in participating in this study. However, by participating, they can contribute to the acquisition of scientific knowledge and the development of new therapeutic targets and novel disease management strategies. Such strategies might benefit patients and mutation carriers in the future if they potentially develop advanced disease. There are no risks associated with the study. There are no interventions other than those related to the regular patient care (venipuncture). Thus, this study is considered to impose a low burden on patients.

• Study Type: Observational
• Enrollment (Estimated): 200

Contacts and Locations

• Study Contact: Name: Kai Xu, M.D.; Phone Number: +316 42385270; Email: kai.xu@radboudumc.nl
• Study Contact Backup: Name: Marieke de Laat, M.D. PhD; Phone Number: +3124 361 4599; Email: marieke.delaat@radboudumc.nl

Study Locations

• Netherlands
  • Gelderland
    • Nijmegen, Gelderland, Netherlands, 6525 GA
      • Recruiting
      • Radboudumc
      • Contact: Marieke de Laat, MD, PhD; Phone Number: +31 24364599; Email: marieke.delaat@radboudumc.nl
      • Contact: Henri Timmers, MD, PhD; Phone Number: +31 24364599; Email: henri.timmers@radboudumc.nl
      • Principal Investigator: Marieke de Laat, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

For part I, the study population will consist of patients who are presenting or are currently under follow-up at the Radboudumc endocrinology department for their PPGL. Eigthy patients will be included with hereditary or sporadic cases of PPGL and an equal number of asymptomatic carriers. The healthy control group will consist of 40 age and sex matched healthy volunteers.

Part II will include histological samples of 160 patients with PPGL, of which 80 hereditary and 80 sporadic. A large part of the population will overlap between part I and part II, since almost all patients with PPGL undergo surgery for their tumour. These samples will partly be retrospectively collected from the Radboudumc Urology Biobank, where biomaterials from previously treated patients with PPGLs are kept and stored or future scientific research (Human Subjects Review Board approval number: CWOM-9803-0060). The remaining samples will be collected prospectively from patients undergoing surgery for their PPGL.

Description

Inclusion Criteria:

Part I:

• Newly diagnosed patients with PPGL or newly diagnosed patients with (metastatic) PPGL recurrence.
• OR patients with mutations which predispose for the development of PPGL.
• Aged > 18 years.

Part II:

• Confirmed PPGL on pathology.
• Aged > 18 years.

Exclusion Criteria:

• Unable to provide informed consent.
• Active inflammatory or infectious comorbidities.
• Other malignancies which are under active treatment (except for basal cell carcinoma, other in situ carcinomas).
• Using medication interfering with the immune system
• Pregnancy or breastfeeding
• A self-reported alcohol consumption of >21 units per week

Study Plan

How is the study designed?

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Patients with hereditary PPGL; Blood will be collected prior and after surgery for their pheochromocytoma/paraganglioma (as planned by their treating physician). Blood will also be collected prospectively during regular follow-up appointments after 1 year and after 2 years.	Procedure: Venepuncture; Blood draw in the context of routine patient care, when a venipuncture is already scheduled.; Procedure: Venepuncture; Volunteering for blood draw.
Patients with sporadic PPGL; Blood will be collected prior and after surgery for their pheochromocytoma/paraganglioma (as planned by their treating physician). Blood will also be collected prospectively during regular follow-up appointments after 1 year and after 2 years.	Procedure: Venepuncture; Blood draw in the context of routine patient care, when a venipuncture is already scheduled.; Procedure: Venepuncture; Volunteering for blood draw.
Asymptomatic carriers of germline mutations predisposing for PPGL; Blood will be collected at inclusion, after 1 year and after 2 years.	Procedure: Venepuncture; Blood draw in the context of routine patient care, when a venipuncture is already scheduled.; Procedure: Venepuncture; Volunteering for blood draw.
Sex and age matched healthy volunteers; Blood material will be obtained from healthy anonymous donors according to the protocol "Donation of blood by healthy volunteers for experimental in-vitro research" (Human Subjects Review Board approval number: NL84281.091.23).	Procedure: Venepuncture; Blood draw in the context of routine patient care, when a venipuncture is already scheduled.; Procedure: Venepuncture; Volunteering for blood draw.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Immune cell response in circulation, both after stimulation and in an unstimulated state, measured as the concentration of inflammatory molecules and proteins.	e.g. cytokines	Before surgery, 6 weeks after surgery, after 1 year, after 2 years.
Immune cell composition in histological PPGL specimens and in circulation.		Before surgery, 6 weeks after surgery, after 1 year, after 2 years. Histological specimens will only be obtained during surgery.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Transcriptional and epigenetic signature of circulating immune cells.		Before surgery, 6 weeks after surgery, after 1 year, after 2 years.
Concentration of immunomodulating metabolites in circulation.	e.g. catecholamines, succinate.	Before surgery, 6 weeks after surgery, after 1 year, after 2 years.
Trained immunity assessment of circulating immune cells.		Before surgery, 6 weeks after surgery, after 1 year, after 2 years.
Tumour recurrence rate		After 1 year, after 2 years.
Metastasis rate		Before surgery, after 1 year, after 2 years.
Survival rate		After 1 year, after 2 years.

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Investigators: Principal Investigator: Margo Dona, PhD, Radboud University Medical Center; Principal Investigator: Henri Timmers, M.D. PhD, Radboud University Medical Center; Principal Investigator: Romana Netea-Maier, M.D. PhD, Radboud University Medical Center; Principal Investigator: Marieke de Laat, M.D. PhD, Radboud University Medical Center

Publications and helpful links

General Publications

• Lenders JW, Eisenhofer G, Mannelli M, Pacak K. Phaeochromocytoma. Lancet. 2005 Aug 20-26;366(9486):665-75. doi: 10.1016/S0140-6736(05)67139-5.
• Cascon A, Calsina B, Monteagudo M, Mellid S, Diaz-Talavera A, Curras-Freixes M, Robledo M. Genetic bases of pheochromocytoma and paraganglioma. J Mol Endocrinol. 2023 Jan 24;70(3):e220167. doi: 10.1530/JME-22-0167. Print 2023 Apr 1.
• Jhawar S, Arakawa Y, Kumar S, Varghese D, Kim YS, Roper N, Elloumi F, Pommier Y, Pacak K, Del Rivero J. New Insights on the Genetics of Pheochromocytoma and Paraganglioma and Its Clinical Implications. Cancers (Basel). 2022 Jan 25;14(3):594. doi: 10.3390/cancers14030594.
• Tufton N, Hearnden RJ, Berney DM, Drake WM, Parvanta L, Chapple JP, Akker SA. The immune cell infiltrate in the tumour microenvironment of phaeochromocytomas and paragangliomas. Endocr Relat Cancer. 2022 Sep 19;29(11):589-598. doi: 10.1530/ERC-22-0020. Print 2022 Nov 1.
• Gao X, Yamazaki Y, Pecori A, Tezuka Y, Ono Y, Omata K, Morimoto R, Nakamura Y, Satoh F, Sasano H. Histopathological Analysis of Tumor Microenvironment and Angiogenesis in Pheochromocytoma. Front Endocrinol (Lausanne). 2020 Nov 10;11:587779. doi: 10.3389/fendo.2020.587779. eCollection 2020.
• van der Heijden CDCC, Groh L, Keating ST, Kaffa C, Noz MP, Kersten S, van Herwaarden AE, Hoischen A, Joosten LAB, Timmers HJLM, Netea MG, Riksen NP. Catecholamines Induce Trained Immunity in Monocytes In Vitro and In Vivo. Circ Res. 2020 Jul 3;127(2):269-283. doi: 10.1161/CIRCRESAHA.119.315800. Epub 2020 Apr 3.
• Nolting S, Bechmann N, Taieb D, Beuschlein F, Fassnacht M, Kroiss M, Eisenhofer G, Grossman A, Pacak K. Personalized Management of Pheochromocytoma and Paraganglioma. Endocr Rev. 2022 Mar 9;43(2):199-239. doi: 10.1210/endrev/bnab019. Erratum In: Endocr Rev. 2022 Mar 9;43(2):440. doi: 10.1210/endrev/bnab044. Endocr Rev. 2022 Mar 9;43(2):437-439. doi: 10.1210/endrev/bnab045.

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2024
• Primary Completion (Estimated): June 1, 2029
• Study Completion (Estimated): June 1, 2029

Study Registration Dates

• First Submitted: May 22, 2024
• First Submitted That Met QC Criteria: May 30, 2024
• First Posted (Actual): June 5, 2024

Study Record Updates

• Last Update Posted (Estimated): November 21, 2024
• Last Update Submitted That Met QC Criteria: November 18, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: Pheochromocytoma; Tumor microenvironment; Innate immunity; Paraganglioma
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Pheochromocytoma; Paraganglioma
• Other Study ID Numbers: 115703

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data will be made available by the corresponding author upon reasonable request.
• IPD Sharing Time Frame: One year after completion of the study.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

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