ACTivating the Immune Response in Ovarian CaNcer
- Conditions
- Ovarian NeoplasmsOvarian CancerOvarian CarcinomaImmune SuppressionImmune System Suppression
- Interventions
- Procedure: Bone marrow aspirationProcedure: Vena punctureProcedure: Peritoneal fluidProcedure: Spleen biopsyProcedure: Tumor biopsy
- Registration Number
- NCT06611072
- Lead Sponsor
- Gynaecologisch Oncologisch Centrum Zuid
- Brief Summary
The goal of this multi-center explorative cross-sectional study is to characterize and phenotype the immune state of ovarian cancer (OC) patients compared to controls without cancer, thereby focusing on the hematopoietic organs and the immune cells originating from these organs. This will be executed by assessing the transcriptional, epigenetic, and functional programming of circulating monocytes and myeloid progenitor cells in OC.
It is hypothesized that OC and its progression are heavily influenced by myeloid cells and their progenitors, mainly through defective trained immunity responses. It is hypothesized that OC patients suffer from a suppressive trained immunity phenotype.
Researchers will compare (1) patients with OC who undergo primary debulking surgery and (2) patients with OC who undergo interval debulking surgery to (3) controls as blood and bone marrow donors to see if there are differences between the transcriptional, epigenetic, and functional signature of i) circulating and intra-abdominal monocytes and ii) bone marrow and spleen myeloid progenitor cells.
Participants will get a:
* Vena puncture
* Bone marrow aspiration
* Tumor biopsy (only cases)
* Spleen biopsy (only cases)
Furthermore, peritoneal fluid will be sent for analysis in all patients.
- Detailed Description
DESCRIPTION OF THE PROBLEM
Ovarian cancer (OC) is one of the most lethal cancers due to late-stage of disease at diagnosis. Standard therapy consists of debulking surgery and chemotherapy. However, despite this aggressive treatment, recurrent disease almost invariably occurs resulting in a five-year survival rate of approximately 30%. Immunotherapy could be a way to increase survival in OC patients. However, a major barrier to a successful deployment of cancer immunotherapy for ovarian cancer patients is the immunosuppressive tumor microenvironment.
RESEARCH DIRECTION
Tumor-related inflammation is one of the hallmarks of cancers in general. Innate immunity specifically is a common denominator that is involved in the pathogenesis of OC. To improve the patient's outcome and identify novel therapeutic targets, one needs a deeper understanding of the tumor-induced changes in the bone marrow myeloid progenitor cells.
HYPOTHESIS
It is hypothesized that OC and its progression are heavily influenced by myeloid cells and their progenitors, mainly through defective trained immunity responses. It is hypothesized that OC patients suffer from a suppressive trained immunity phenotype. In the future, therapeutic targeting of trained immunity could be explored to develop novel immunotherapies for tumors that are refractory to conventional treatment.
OBJECTIVE
To characterize and phenotype the immune state of OC patients compared to controls without cancer, thereby focusing on the hematopoietic organs and the immune cells originating from these organs.
This will be executed by assessing the transcriptional, epigenetic, and functional programming of circulating monocytes and myeloid progenitor cells in OC.
STUDY DESIGN
Investigator-initiated, multi-center explorative cross-sectional study at the Catharina hospital Eindhoven, Radboud University Medical Center and Eindhoven University of Technology.
STUDY POPULATION
The following patients will be included in the study:
* Group 1. Patients with OC who undergo primary debulking surgery (N=30)
* Group 2. Patients with OC who undergo interval debulking surgery (N=30)
* Group 3. Controls as blood and bone marrow donors (N=30)
MAIN STUDY PARAMETERS/ENDPOINTS
Primary endpoints: transcriptional, epigenetic, and functional signature of circulating monocytes and myeloid progenitors. For transcriptional markers, differentially expressed genes between the different groups will be the focus, with a particular emphasis on antigen presentation and processing pathways, inflammatory pathways (e.g., NF-kB), metabolic pathways and enzymes, and pattern-recognition receptor (PRR) signal transduction. For epigenetic markers, the focus will be on three histone marks positively associated with gene expression and trained immunity: H3K4me3, which marks promoters; H3K4me1, which marks distal regulatory elements (enhancers); and H3K27ac, which marks active promoters and enhancers. For functional markers, the focus will be on the degree of trained immunity response in vitro.
Recruitment & Eligibility
- Status
- NOT_YET_RECRUITING
- Sex
- Female
- Target Recruitment
- 90
- Subjects should be at least 18 years old and mentally competent;
- Newly diagnosed patients with OC who go for primary debulking surgery or patients with OC who are scheduled for interval debulking;
- Controls: women who undergo surgery for benign gynaecological conditions under general anaesthesia.
- Mentally incompetent;
- Pregnant or breastfeeding;
- Known inflammatory of infectious diseases or an immunosuppressive status;
- Using medication interfering with the immune system;
- Severe comorbidities: other active malignancy (except for basal cell carcinoma and other in situ carcinomas);
- Serious psychiatric pathology;
- A self reported alcohol consumption of >21 units per week.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Group 1 Bone marrow aspiration Patients with OC who undergo primary debulking surgery Group 1 Vena puncture Patients with OC who undergo primary debulking surgery Group 1 Peritoneal fluid Patients with OC who undergo primary debulking surgery Group 1 Spleen biopsy Patients with OC who undergo primary debulking surgery Group 1 Tumor biopsy Patients with OC who undergo primary debulking surgery Group 2 Bone marrow aspiration Patients with OC who undergo interval debulking surgery Group 2 Vena puncture Patients with OC who undergo interval debulking surgery Group 2 Peritoneal fluid Patients with OC who undergo interval debulking surgery Group 2 Spleen biopsy Patients with OC who undergo interval debulking surgery Group 2 Tumor biopsy Patients with OC who undergo interval debulking surgery Group 3 Bone marrow aspiration Controls as blood and bone marrow donors Group 3 Vena puncture Controls as blood and bone marrow donors Group 3 Peritoneal fluid Controls as blood and bone marrow donors
- Primary Outcome Measures
Name Time Method Cell composition of immune organs using flow cytometry 3 years including evaluation phase The number and ratios of different types of stem and immune cells will be determined using general cell protein markers in combination with flow cytometry. Analysis will be performed on blood, spleen, bone marrow and the intraperitoneal fluid.
Cell composition and epigenetic status of cells of immune organs using ATAC and RNA sequencing 3 years including evaluation phase Cell ratios and epigenetic profile of immune cells in the blood, tumor, bone marrow, and spleen will be analyzed using single-cell RNA and single-cell ATAC sequencing.
- Secondary Outcome Measures
Name Time Method
Trial Locations
- Locations (1)
Catharina Hospital
🇳🇱Eindhoven, Brabant, Netherlands