The goal of the research activities at the Laboratory for Molecular and Cellular Therapy (LMCT) is to develop innovative immunotherapy strategies. The strategies under development include (1) ex vivo and in vivo engineering of dendritic cells for immune activation and (2) engineering of the tumor microenvironment to facilitate antitumor immune responses. Technologies such as mRNA, lentiviral vectors and single domain antibodies (better known as nanobodies) are employed for these purposes. Strategies under development are extensively tested in preclinical in vitro models using cells of human and mouse origin as well as in mouse cancer models. Successful strategies are translated towards clinical applications in phase I/II trials.
Since tumor cells and their environment exploit a plethora of mechanisms to inhibit antitumor immune responses, LMCT’s research, under the impulse of Prof. Karine Breckpot, has extended to designing strategies to study and counteract immunosuppressive mechanisms in the tumor microenvironment. Dendritic cells can present tumor antigens to T cells and as such activate the latter to search for and destroy tumor cells. Today it is recognized that activation of T cells by dendritic cells was a major step forward in the treatment of cancer. However, tumor cells create an environment in which they can thrive and in which they collaborate with suppressive immune cells to counteract antitumor immune responses. Therefore, it is generally accepted that an effective immunotherapy has to be multifaceted, aiming at stimulation of T cell responses, whilst reprogramming the immunosuppressive tumor microenvironment. Lentiviral vectors are being used to directly manipulate tumor cells, evaluating strategies to induce tumor cell death or knock out molecules critical for the progression of tumor cells. Also mRNA is extensively studied to engineer the tumor microenvironment, delivering proteins with immunomodulating properties, including fusokines and TriMix. More recently, nanobodies have been studied for both imaging of immune cells and markers in the tumor environment as well as their modulation with a focus on myeloid cells and inhibitory immune checkpoints.
Although our immune system is capable of discriminating healthy cells from tumor cells, it has failed in destroying tumor cells in cancer patients. Therefore, medical science has focused on the development of several strategies that aid the immune system in the surveillance and elimination of tumor cells. Dendritic cells are ‘the professional’ antigen-presenting cells of our immune system and are recognized as key players in the instigation of immune responses. Much effort has been put in their exploitation in immunotherapy for cancer. Instigated by Professor Kris Thielemans, the LMCT developed different strategies to genetically modify dendritic cells. A first extensively studied platform uses mRNA to reprogram dendritic cells. This approach has successfully been evaluated for ex vivo as well as in vivo modification of dendritic cells. The TriMix technology platform has been developed specifically for this approach and allows optimizing the stimulatory capacity of dendritic cells. The use of the TriMix technology represents a turning point in the quest for an effective dendritic cell-based immunotherapy. A second platform uses lentiviral vectors, HIV-1 derived vectors, for ex vivo and in situ modification of dendritic cells. The nanobody-display technology was developed to target lentiviral vectors to dendritic cells in situ.