OveRcoming immunosupprEssion aNd rebAlancing the Immune reSponSe in ovAriaN CancEr Study

Summary

Ovarian cancer (OC) is one of the most lethal cancers in the world due to late-stage 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.

Envisioned solution/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. Furthermore, treatment of these cells by nanoparticles or other agents that induce a program of 'trained immunity' may be a novel way to re- educate myeloid cells and their bone marrow progenitors in OC patients.

Hypothesis

We hypothesize that by exposing myeloid cells or their progenitors to various agents that induce trained immunity (e.g. trained immunity-inducing agents: BCG, heat-killed Candida,), these immune cells will undergo functional reprogramming to induce a tumor-suppressive phenotype. In the future, this could be explored as a novel immunotherapy for tumors that are refractory to conventional treatment.

Objective

To characterize and phenotype the immune state of OC patients compared to controls without cancer with a focus on the hematopoietic organs and the immune cells originating from these organs. In addition, the effect of established trained immunity-inducing agents on these cells will be evaluated in vitro, potentially providing new therapies.

This will be executed by assessing the transcriptional, epigenetic, and functional reprogramming of circulating monocytes and myeloid progenitor cells in OC and by assessing the in vitro effect of trained immunity inducers on the reprogramming of circulating monocytes and myeloid progenitor cells.

Study design: investigator-initiated, multi-center explorative cross-sectional study at the Catharina hospital Eindhoven, Radboud University Medical Center and Eindhoven University of Technology.

Conditions

• Ovarian Neoplasms
• Ovarian Cancer
• Ovarian Carcinoma
• Immune Suppression
• Immune System Suppression

Interventions

PROCEDURE

Bone marrow aspiration

Bone marrow samples will be obtained from the sternum or the iliac crest according to standard practice by experienced operators during the surgery patients will undergo as part of their medical treatment. BM mononuclear cells will be isolated using Ficoll-Paque and progenitor cells will be enriched using positive selection with CD34 beads by MACS. Progenitor cell composition will be identified using flow cytometry. HSPC proliferation assays (standard CFU assays) to assess myeloid colony-forming potential will be performed. In addition, single-cell RNA- sequencing and epigenetic assessment (ATAC-seq, ChIP-seq, DNA methylation) will be performed.

PROCEDURE

Vena puncture

Whole blood will be collected and peripheral blood mononuclear cells (PBMC) will be isolated using Ficoll-Paque. Cellular subpopulations will be purified using negative selection of monocytes with PanMonocyte beads by MACS.

PROCEDURE

Peritoneal fluid

Peritoneal fluid will be collected during the surgery.

PROCEDURE

Spleen biopsy

Spleen samples will be obtained by experienced surgeons during the debulking surgery. Spleen mononuclear cells will be isolated using Ficoll-Paque and progenitor cells will be enriched using positive selection with CD34 beads by MACS. Cellular subpopulations will be further purified using negative selection of monocytes with PanMonocyte beads by MACS. Progenitor cell composition will be identified using flow cytometry. HSPC proliferation assays (standard CFU assays) to assess myeloid colony-forming potential will be performed. In addition, single- cell RNA-sequencing and epigenetic assessment (ATAC-seq, ChIP-seq, DNA methylation) will be performed.

PROCEDURE

Tumor biopsy

During debulking surgery, all visible tumor tissue will be removed by experienced surgeons.

PROCEDURE

Omental biopsy

During debulking surgery, an omental biopsy will be done.

Sponsors & Collaborators

• Eindhoven University of Technology

  collaborator OTHER

• Radboud University Medical Center

  collaborator OTHER

• Gynaecologisch Oncologisch Centrum Zuid

  lead OTHER

Study Design

Allocation

NON_RANDOMIZED

Purpose

OTHER

Masking

NONE

Model

PARALLEL

Eligibility

Min Age

18 Years

Sex

FEMALE

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2025-01-01

Primary Completion

2027-10-31

Completion

2027-12-31

Countries

• Netherlands

Study Locations