Research Jorrit De Waele

Abstract

Cellular cancer immunotherapy is on the rise to follow the footsteps of immune checkpoint inhibition as cancer immunotherapy breakthrough, yet only shows efficacy in haematological malignancies. Indeed, solid tumours impose various challenges on immune cells. Their tumour microenvironment (TME) is a metabolic wasteland that impairs effector immune cell functioning. Central in this TME is hypoxia, which is now recognized as barrier to immunotherapy due to effects on both tumour and immune cells. In this project, we focus on natural killer (NK) cells as effector immune cells with great potential as adoptive cell product due to inherent cytolytic capacities as well as safety and logistics profiles. Nonetheless, even when armoured with chimeric antigen receptors (CAR), NK cells fail to fully exert their function in hypoxia. Here, we will characterize and validate our lead for the development of (CAR) NK cells proficient in the hypoxic TME. This could propagate the development of next-generation of metabolically enhanced CAR NK cells against solid tumours.

Researcher(s)

• Promoter: De Waele Jorrit

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

In the past five years, RNA therapeutics have witnessed a true revolution. Several RNA-based therapies have been approved for the treatment of genetic diseases, with unprecedented successes, as in spinal muscular atrophy. Moreover, the past year showed the world that RNA-based therapies, namely mRNA vaccines, can be the answer to a worldwide pandemic and save the lives of millions. RNA therapies are however lagging behind in clinical oncology. The overarching aim of this multi-armed project is to develop RNA-based cancer treatments. In parallel, the development of immune checkpoint inhibitors has revolutionized cancer care, but its success remains limited to a subset of patients. Altogether, for 60 percent of the eight million new cancer patients diagnosed in Europe each year, including almost all children with solid tumors, there is no EMA- or FDA-approved immunotherapy option, and they are left out of the circle of hope. In response, CANCERNA aims to build on these two breakthroughs and apply RNA-based therapeutics to overcome key barriers to unfold successful anti-cancer immune responses. Our two key objectives are: on one hand, harness the modulation of RNA processing to enhance the accessibility and immune susceptibility of the tumour and its microenvironment. While on the other hand, enhance the activity of the immune system by retargeting immune effector cells and developing personalized mRNA vaccines. The project will focus on two cancer types: acute myeloid leukemia and uveal melanoma. The collective knowledge of our consortium of RNA scientists, clinicians and biotech-pharma experts in RNA processing, RNA drug design and delivery, biocomputing and immuno-oncology provides a unique opportunity to significantly advance novel RNA technologies into successful cancer therapies.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: De Waele Jorrit
• Co-promoter: Lion Eva
• Co-promoter: Pauwels Patrick
• Co-promoter: Siozopoulou Vasiliki
• Co-promoter: Van Audenaerde Jonas

Research team(s)

• Center for Oncological Research (CORE)

Project website

Project type(s)

• Research Project

Abstract

Breast cancer (BC) and cervical cancer (BHK) patients, especially those with advanced disease, are in urgent need of new agents that improve survival and quality of life. One promising strategy is immunotherapy, but the cancer has developed mechanisms that circumvent its effects and benefit only a minority of patients. Recently, the RANK(L) signaling pathway is considered a significant mechanism, as it allows many cancers - including BK and BHK - to disrupt the communication of the immune cells and thus undermine the immune response. Supported by our initial results, we strongly believe that blocking this signal can override the immune system and improve susceptibility to immunotherapy. We therefore seek to reveal the most appropriate anti-RANK(L) immunotherapy to elicit an optimal anti-tumor immune response. Building on the results of our clinical studies, additional laboratory testing will allow us to identify that one, superior combination strategy, which we will further optimize in mouse models. Finally, this project will validate a novel imaging technique to select patients who will benefit from this therapy in order to minimize treatment and financial burden.

Researcher(s)

• Promoter: Van Dam Peter
• Co-promoter: De Waele Jorrit
• Co-promoter: Lardon Filip
• Co-promoter: Prenen Hans
• Co-promoter: Smits Evelien
• Co-promoter: Van den Wyngaert Tim

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Cervical cancer (CC) patients, especially those with advanced disease, are urgently in need of new treatment options that can increase their survival rate and quality of life. A promising strategy is immunotherapy, however, only a minority of patients responds to it because the cancer has developed mechanisms that evade its effects. In recent years, the RANKL/RANK signaling pathway has been implicated as one such mechanism, as it allows many cancer types - including CC - to circumvent the immune response by disrupting the communication of the immune cells. Supported by our first results, we strongly believe that blocking the RANKL/RANK signal can release the brakes on the immune system and reinvigorate the tumor's susceptibility to immunotherapy. We therefore aim to expose the best possible immunotherapeutic partner(s) for anti-RANK(L) therapy in order to achieve the most optimal anti-tumor immune effects. For this, we have unique access to CC samples retrieved from patients before and after anti-RANKL monotherapy, which we will thoroughly investigate to reveal immune related changes. Thereafter, we will perform additional laboratory tests that will allow us to pinpoint one best-in-class anti-RANKL combination strategy, which we will further optimize in CC mouse models. Finally, this project will validate a novel imaging technique to stratify patients and monitor treatment response for this therapy, thereby minimizing treatment - and economic burden.

Researcher(s)

• Promoter: Van Dam Peter
• Co-promoter: De Waele Jorrit
• Co-promoter: Van den Wyngaert Tim
• Fellow: Verhoeven Yannick

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Acute myeloid leukemia (AML) is a hematological cancer that arises and spreads from the bone marrow. It has a very dismal prognosis, characterized by a high relapse rate, despite initial complete molecular remission. Residual leukemic stem cells (LSC) are believed to be to origin of this relapse. LSC reside in a tumoral bone marrow that features a heightened state of hypoxia. Immunotherapeutic strategies are on the rise and are promising approaches to go hunt-and-destroy LSC. However, they will have to overcome the hypoxic burden in the leukemic bone marrow. Indeed, hypoxia is nowadays recognized as a barrier for immunotherapy. In this project, we will focus on natural killer (NK) cells as a born killer with great potential as adoptive cell product. While cytokines and chimeric antigen receptors (CAR) have improved the cytotoxic potency and targetability of NK cell products, their effectiveness at the tumor site is incapacitated by hypoxia. To address this conundrum, we will investigate several approaches to metabolically sustain their killing capacity in hypoxia in order to elicit potent elimination of both LSC and differentiated AML cells in the leukemic bone marrow. This will open up opportunities to develop next-generation CAR NK cells as an available off-the-shelf product for the treatment of AML patients.

Researcher(s)

• Promoter: De Waele Jorrit
• Co-promoter: Smits Evelien
• Co-promoter: Wouters An

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

We will study the contribution of hypoxia-inducible factors (HIF) to innate immunosuppression in glioblastoma (GBM) in hypoxia. The capacity of HIF inhibitors combined with an immunostimulant to eliminate GBM cells will be studied in hypoxic cocultures of human GBM cells, natural killer cells and macrophages. This study will elucidate mechanisms of GBM-mediated immunosuppression and will generate valuable new insights for the development of novel efficacious immunotherapeutic strategies to treat GBM.

Researcher(s)

• Promoter: De Waele Jorrit

Research team(s)

Project type(s)

• Research Project

Abstract

We will study the contribution of hypoxia-inducible factors (HIF) to innate immunosuppression in glioblastoma (GBM) in hypoxia. The capacity of HIF inhibitors combined with the immunostimulant poly(I:C) to eliminate GBM cells will be studied in hypoxic cocultures of human GBM cells, natural killer cells and macrophages. This study will elucidate mechanisms of GBM-mediated immunosuppression and will generate valuable new insights for the development of novel efficacious immunotherapeutic strategies to treat GBM.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: Berneman Zwi
• Co-promoter: Peeters Marc
• Fellow: De Waele Jorrit

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

We will study the contribution of hypoxia-inducible factors (HIF) to innate immunosuppression in glioblastoma (GBM) in hypoxia. The capacity of HIF inhibitors combined with the immunostimulant poly(I:C) to eliminate GBM cells will be studied in hypoxic cocultures of human GBM cells, natural killer cells and macrophages. This study will elucidate mechanisms of GBM-mediated immunosuppression and will generate valuable new insights for the development of novel efficacious immunotherapeutic strategies to treat GBM.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: Berneman Zwi
• Co-promoter: Peeters Marc
• Fellow: De Waele Jorrit

Research team(s)

Project type(s)

• Research Project

Abstract

Glioblastoma is the most common, malignant, primary brain tumor. One of the characteristics of this (and other) cancer(s) is suppression of the immune system. The aim of this research is to (re )activate the antitumoral functions of the innate immune cells in glioblastoma. This will be achieved by combining direct stimulation of the innate immune cells with alleviation of the protumoral and immunosuppressive tumor microenvironment.

Researcher(s)

• Promoter: Smits Evelien
• Fellow: De Waele Jorrit

Research team(s)

Project type(s)

• Research Project