Therapy concept

Immune cells surveil the body for foreign intruders such as bacteria and viruses, as well as for cells that act abnormally and/or die, for instance as a result of a viral infection or cancer. Upon encounter of such abnormalities, immune cells eliminate the intruders and the cells affected, call in help from additional immune cells (the inflammatory response), and clean up the debris. While this immune reactivity is essential for our survival, it is equally important that the immune system does not always kick in when cells die (e.g. during normal tissue renewal) or when foreign substances are encountered (e.g. in food or harmless substances like pollen). Uncontrolled reactions of immune cells can be the cause of auto-immune diseases (e.g. rheumatoid arthritis) and allergies.

In order to avoid unwanted inflammatory responses, all immune cells are equipped with receptors at their surface that function as ‘on’ and ‘off’ switches. In principle, immune cells will only respond to foreign intruders or abnormal cells if they receive additional ‘on’ signals, while the presence of strong ‘off’ signals can suppress their reactivity. For instance, during infection of the lung with Influenza virus, the presence of the virus does not only result of substances (antigens) that are foreign to the immune system, but also in the destruction of cells that are infected by the virus. This ‘mess’ of antigens and tissue damage constitutes a strong ‘on’ signal for immune cells, including T-lymphocytes that can orchestrate the destruction of virus-infected cells, so that no more virus is produced, and the clearance of infectious viral particles.  In this manner, many viral infections can be controlled before the infection becomes life threatening.

T-lymphocytes are in principle also highly capable of destroying tumors and preventing cancer. The main problem with cancer is that tumors usually develop from a single, genetically modified (mutated) cell that starts to multiply in an unregulated fashion. Out of this first tumor cell, a tumor gradually develops. Unlike a viral infection, cancer development is a stealthy process that is usually not noticed by the immune system until the tumor starts to disturb the physiological functions of the tissue in which it arises. Moreover, during this initial tumor development, the immune system gets used (tolerized) to the emerging tumor due to immunoregulatory ‘off’ signals that also prevent unwanted overreactions by the immune system. The ‘off’ signals are essential for preventing autoimmune diseases, but can also help the tumor to escape immune detection and destruction.

Nevertheless, in many cancers some arousal of the immune system is taking place during cancer development, especially when the tumor becomes larger. This results in what one could consider a ‘tumor-observing’ immune response that is sufficient to slow down tumor development, but insufficient to tip the balance in favor of the immune defense and cause tumor regression.

Over the past 20 years, our insight in the ‘on’ and ‘off’ signals that regulate the immune system, has greatly advanced, in particular by in depth experiments in mice. As a result of this work, approaches have been developed to activate immune cells by blocking ‘off’ signals and/or by providing artificial ‘on’ signals. In mouse models for cancer, this has resulted in strong T-cell responses capable of destroying tumors. In many of these experiments, the modification of these ‘on’ and ‘off’ signals was done by using antibodies specific for surface receptors on T-lymphocytes. Antibodies that block inhibitory ‘off’ receptors were shown to take the break of pre-activated tumor-reactive T-cells. Antibodies that bind and stimulate activatory ‘on’ receptors were shown to activate tumor reactive immune cells by providing the ‘on’ signals that are missing in the tumor.

In 2010, the pre-clinical findings with one of the blocking antibodies was translated into a clinically approved drug that was capable of activating the anti-tumor T-cell response in a subset of cancer patients: the antibody Ipilimumab/Yervoy. More recently, two additional blocking antibodies that target a different ‘off’ receptor on T-cells were also clinically approved: Nivolumab/Opdivo and Pembrolizumab/Keytruda.

Importantly, the pre-clinical findings with antibodies that activate anti-tumor immunity by delivering ‘on’ signals to activatory receptors still await translation into clinically approved drugs. This translation is essential, because the blocking antibodies are not effective in all cancer types and/or all patients with a given type of cancer. This is due to the fact that the failure of anti-tumor immunity can be the result of various mechanisms. It is therefore important to develop a broad array of immunostimulatory drugs that can activate immune cells by different mechanisms. The mission of the IACT consortium is to increase the number of immunostimulatory drugs available to cancer patients by clinical development of antibodies that deliver ‘on’ signals by binding to three well-defined activatory immune receptors.