Overview
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.
Description
INTRODUCTION AND RATIONALE
Problem description:
Ovarian cancer is the fifth leading cause of cancer death among women in the Western world. The high mortality rate is due to detection at an advanced stage of the disease and lack of curative therapies. Standard therapy consists of a combination of cytoreductive surgery and chemotherapy. Despite this aggressive treatment, recurrent disease almost invariably occurs resulting in a five-year survival rate of only 30%, which has not changed significantly over the last 30 years.
Recurrent ovarian cancer is generally treated with second/third line chemotherapy, and (costly) targeted therapies. Although targeted therapy options are rapidly expanding, response rates often fall short of expectations probably caused by heterogeneity of the disease. Therefore, new treatment options need to be explored. One such option is immunotherapy. However, the limited data on this topic show disappointing results.
Envisioned solution/research direction:
To improve the patients' outcomes and identify novel therapeutic targets, one needs a 'systems understanding' of the pathophysiology of tumors, which transcends beyond the process of carcinogenesis to encompass the complex interaction of the malignant cells with other cell types in the tumor and the tumor environment (TME), especially immune cells. The inflammatory TME has characteristics that promote and support the malignant phenotype, and inflammatory pathways have been proposed as new targets for cancer therapy. The TME conditions the local myeloid cells to become immunosuppressive. In this project we primarily focus on myeloid cells, in particular circulating monocytes and their progenitors, as well as the tumor-
associated macrophages (TAMs) which are pluripotent myeloid cells that represent the most abundant component of the TME in advanced OC arguing for their importance in the pathogenesis of OC.
In the present study, we aim to investigate the programming of myeloid cells in OC patients with advanced tumors in depth and to explore whether we can functionally reprogram myeloid cells from different bodily compartments (circulating monocytes, bone marrow (BM) and spleen progenitors) towards an anti-tumorigenic phenotype by trained immunity-modulating nanoparticles. If this hypothesis is proven to be correct, this mechanism could be explored in further studies including investigation of the interaction of myeloid cells with other immune cells and as a novel immunotherapy for OCs that are refractory to conventional treatment.
OBJECTIVES
To assess the transcriptional, epigenetic, and functional reprogramming of circulating monocytes and myeloid progenitor cells in OC by in vitro exposure to agents that modulate trained immunity.
To achieve this goal the study has a set of complementary Key objectives:
To assess the transcriptional, epigenetic, and functional signature of i) circulating monocytes in patients with OC compared to controls in response to trained immunity inducers in vitro and ii) bone marrow and spleen myeloid progenitor cells in patients with OC compared to controls in response to trained immunity inducers in vitro.
Eligibility
Inclusion Criteria:
- 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.
Exclusion Criteria:
- 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.