Transcriptomic and phenotypic profiling of the white blood cells in breast cancer

Despite considerable improvements in breast cancer management, approximately one in four patients still die due to metastases. In order to decrease this mortality, the disease needs to be diagnosed as early as possible, and metastases must be prevented or treated effectively. Studies we have conducted show that the presence of breast cancer alters quantifiable phenotypic and transcriptomic characteristics of white blood cells (leucocytes) circulating in the blood. These results suggest that it may be possible to exploit these changes in the leucocytes circulating in the blood to reveal the presence of primary breast cancer (screening) or a relapse (monitoring).

The aim of our project is to generate additional data supporting these observations. To this end, we will use novel approaches and technologies (single cell RNA sequencing and multi-parameter analysis of the cell surface). We plan to compare first-diagnosis female patients with healthy women, and patients at the time of the first relapse after therapy with patients not having suffered a relapse. We will investigate the three biological subtypes of breast cancer (ER⁺, HER2⁺, triple negative). This multicentric study, conducted in the Lake of Geneva area, will be coordinated at the CHUV in Lausanne.

A 20 ml blood sample will be taken for the following lab tests: i) leucocyte phenotyping by flow cytometry; ii) transcriptomic analysis and phenotyping by single cell RNA sequencing, followed by bioinformatic analyses. The lab tests will be conducted at the University of Fribourg, the sequencing at the Genomic Technologies Facility of the University of Lausanne (LGTF) and the bioinformatic analyses at the Swiss Institute of Bioinformatics (SIB).

We hope that these analyses will help us validate our preliminary observations more precisely and that we will be able to identify candidate biomarkers (cells, phenotypes, gene expression) and combinations associated with primary breast cancer or the first relapse.

This study is part of a long-term goal to develop a cancer screening blood test and a monitoring blood test for early detection of relapses. The practical implications of these tests are potentially significant: the tests could contribute to changing the way women are screened and patients monitored, thereby greatly improving the quality of life of women in general (screening) and of breast cancer patients (monitoring). From a clinical point of view, the monitoring test would be a valuable new tool that could help support therapeutic choices in the treatment of breast cancer.

Project

Development of a novel B cell-based vaccine for metastatic solid cancers

It is now well established that the immune system plays a very important role in controlling tumor growth; in fact, the remarkable results achieved in the past few years with the arrival of cancer immunotherapies and checkpoint inhibitors have clearly revolutionized the field of oncology and have dramatically changed the therapeutic scenario in many tumor types. Among the different cancer immunotherapies now available, cancer vaccines focus on the therapeutic use of a special type of immune cells called antigen-presenting cells (APCs). The main physiological role of these cells is to intercept and recognize pathogen-associated and foreign material (called antigens), and to subsequently initiate an immune response aimed at clearing the original antigen-containing threat from the host. Given the pivotal role played by APCs in orchestrating an immune response, it comes as no surprise that this type of cells has been employed since the infancy of modern cancer immunotherapy in the fight against cancer.

Canonical approaches have so far relied on the use of a special type of APCs called dendritic cells (DCs), which have long been considered the most potent type of APCs in the human body. However, despite proving generally safe and being associated with very mild collateral effects, DC-based therapeutic vaccines have so far demonstrated limited therapeutic efficacy. Mounting evidence now suggests that a second type of APCs called B cells present a valid alternative with several advantages. First of all, B cells can be obtained and expanded in large quantities from the human body, while cell availability often constitutes a limiting factor with DC-based vaccines. Contrary to DCs, B cells are also resistant to functional inhibition induced by tumor-produced factors, another aspect often limiting DC therapeutic efficacy. Several previous studies have also shown that B cells are indeed able to induce a potent and cancer-specific immune response.

Based on this collective evidence, our project focuses on developing a novel therapeutic vaccine against cancer, based on B cells. One of the first project goals is to manipulate and engineer B cells to express special receptors that increase their accumulation at the tumor site after infusion into the patient. This aspect is obviously crucial in improving their efficacy against their tumor targets and in limiting off-side and systemic effects. In a second phase, we will test our B cell vaccine formulation in combination with checkpoint blockade inhibitors, another promising immunotherapy with a different and complementary mode of action. Checkpoint blockade refers to specific pathways normally developed by tumors that inhibit T cell activities, exerting a sort of “break” on the function of the immune system and anti-cancer properties. Thus, combining these two therapies constitutes an interesting potential therapeutic option, in which B cells would activate the immune system (more specifically T cells) against tumor targets, whilst checkpoint blockade inhibition would remove inhibitory “breaks” on T cell function and unleash these cells’ true anti-cancer potential.

In the last part of this project and thanks to the infrastructure for translational studies available at the University Hospital of Lausanne and at the Ludwig Institute (Lausanne Branch), we will also develop protocols and tests for an efficient production of our B cell final formulation in a good manufacturing practices (GMP) context, so as to enable its future application in clinical studies and patient tests. The requirements for testing cellular therapies in patients (usually referred to as GMP conditions) are obviously very different and stricter than laboratory bench and animal research settings, and a great deal of work is usually needed to adapt therapy production in order to meet such requirements. Thus, the validation of the findings of this project in a GMP context will pave the way for future translational studies in cancer patients, and will potentially help advance both the therapeutic scenario and clinical outcomes.

Project Part 1

Project Part 2

Project