Improving therapeutic vaccines
Chemist Sander van Kasteren aims to accurately map how our immune system responds to vaccines, particularly those aimed at curing diseases like cancer and chronic viral infections. The goal is to use this knowledge to improve vaccine design. An ERC Consolidation Grant will provide him with the funding to pursue this research for the next five years.
Activating the immune system
The concept of immune activation to cure cancer and chronic viral infections is gaining a lot of traction. It is possible to trigger the immune system with a therapeutic vaccine to clear pre-existing anomalous cells. The design of these therapeutic vaccines still has much room for improvement. With that aim, Sander van Kasteren investigates how immune cells respond to these therapeutic vaccines.
Destroying aberrant proteins
A therapeutic vaccine contains an aberrant protein that occurs in cancer cells or virus-infected cells. Certain immune cells, the dendritic cells, take up the vaccine and cut the protein into pieces that are loaded onto ‘presentation trays’ and brought to the cell surface. These trays are molecules of the Major Histocompatibility Complex (MHC) type I. Subsequently, the dendritic cells migrate to lymph nodes to present the protein fragments to other immune cells, cytotoxic T cells. They are able to distinguish aberrant protein fragments from normal fragments. If they detect an anomaly, they start to search for cells that display such a foreign protein fragment (all cells present fragments of their protein content) and destroy them.
A timing conundrum
‘There are still many things about those dendritic cells that we don’t understand,’ van Kasteren tells. ‘We have assessed the speed of this uptake process and found it to take minutes to hours for these therapeutic vaccines. The tray-proteins have also been shown to disappear again later on, likely within a few hours. Yet, dendritic cells may need as much as two or three days to reach lymph nodes, where they have to show the fragments to cytotoxic T cells. This timing conundrum is one of the things I want to investigate.’
Modifying a vaccine
Being a chemist, he is going to try chemically modifying a therapeutic vaccine and add chemical switches that start or stop the recognition of protein fragments on dendritic cells by cytotoxic T cells at specific, predefined, times. ‘By varying time intervals, we can investigate when vaccine fragments appear and when they disappear on the dendritic cell surface.’ He also intends to add chemical functionalities to the vaccine that enable him to follow what happens to it within dendritic cells. ‘Until now, we lacked suitable methods for such research.’
Van Kasteren will firstly conduct tests in cell cultures, and subsequently in animal models. ‘The idea is to find out how we can adjust therapeutic vaccines to get better vaccination results. I expect that major improvements will be possible.’
Why is it that therapeutic vaccines perform less well than vaccines intended to prevent diseases, such as measles or rubella vaccines? ‘Preventive vaccines, containing non-self proteins from outside the body, are picked up, processed and presented by other immune cells and on other trays, molecules of the MHC type II. That presentation has been shown to persist for days.’
text: Willy van Strien