CAR T-cell therapy is a form of cancer therapy, which uses genetically modified (immune) T cells to kill cancer cells. If successful, it is curative, unlike other therapies. Failure occurs, often due to T-cell exhaustion. This can be linked to mitochondria, the energy factories of a cell, that can be hijacked by cancer cells . This leads to energy depletion and impaired killing. This study aims to investigate whether mitochondrial transfer occurs when CAR T cells and cancer cells interact, and how this impacts CAR T cell function..

Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis among major malignancies, mainly due to resistance to current therapies, such as gemcitabine based combinations. We established unique primary PDAC cell cultures to evaluate the efficacy of innovative drugs, such as c-Met inhibitors. c-Met plays a pivotal role in regulation of cell proliferation and migration. Inhibitors such as crizotinib were effective in overcoming chemoresistance in these PDAC primary cells. However, these models do not completely reflect PDAC since in vivo the tumor also consists of stromal cells. Therefore 3-dimensional (3D) co-cultures of primary PDAC cells with pancreatic stromal cells will be established as a more realistic PDAC model. Pancreatic stellate cells (PSCs) are the major stromal cells that play a major role in promotion of tumor growth and invasiveness. Next to target these PSCs we also aim to target other “dominant nodes” in PDAC tumorigenesis. This innovative approach will greatly improve development of novel therapies. Dr. Firuzi has outstanding skills in the area of cancer drug discovery with the implementation of in vitro cell models, and his contribution to this NWO grant, will further enhance this research line in our laboratories by building up expertise on new cellular models to test novel targeted therapies. In this 4 months project we will investigate novel inhibitors of the c-MET and AXL (another important receptor tyrosine kinase) pathways. To bypass potential resistance of downstream PI3K/Akt/mTor pathway we will also investigate inhibition of this pathway. We aim to study 2-3 novel inhibitors in each category in our cutting-edge in vitro models of PDAC. We will investigate inhibition of proliferation as well as migration by these inhibitors alone or in combination with gemcitabine by using a standard sulforhodamine-B assay and by scratch and transwell assays, respectively. The effect of the drugs in the 3D co-cultures will be examined by fluorescence microscopy by using primary PDAC cells transduced with mCherry and human PSCs transduced with GFP. This project will establish innovative in vitro models for discovery of novel personalized therapeutics for management of pancreatic cancer

Immunotherapy is currently the most well-studied form of cancer therapy. Cancer vaccines are promising but they only sparsely made it to the clinic. Immune checkpoint inhibition and CAR T cell therapy are also developed as cancer immunotherapy. Both of these have stellar reputations in the treatment of cancer. The goal of this meeting is the interaction – and knowledge exchange – between a series of big-shots in these immunotherapy fields with a broader group of young scientists making a career in these research fields. The subject of the conference is straight in the heart of biomedical science.

Colorectal cancer (CRC) results in almost 900,000 deaths per year despite a large variety of treatment strategies. Therefore, patients need more precise treatments addressing molecular pathways involved in differentiation, proliferation and migration of malignant cells, to improve treatment of CRC or entirely prevent it from developing. Within this project, we propose a new vaccination strategy aimed at inhibiting Wnt signalling, an evolutionary conserved CRC signalling target, followed by validation of the vaccines in both premalignant and advance CRC mouse models, with the aim to pave the way towards the clinic for vaccines that improve both prevention and treatment of CRC.