Epicutaneous vaccination - targeting of Langerhans cells

Dendritic cells are leukocytes that are critically involved in the generation of primary immune responses, typically against microbes such as bacteria and viruses. Dendritic cells are positioned at the beginning of virtually all immune reactions, be they mediated by helper T lymphocytes against intracellular bacteria, or by cytotoxic killer lymphocytes against virus-infected cells, or by antibodies in the serum and in tissues. The immune system can also act against cancer cells. Immune-surveillance mechanisms keep cancer cells in check. When they fail, cancer develops in the body. This key position of dendritic cells is being harnessed for therapeutically inducing anti-cancer immune responses. Clinical studies where dendritic cells from patients` blood are cultured, "loaded" with tumor- specific molecules and injected back into the patient, are conducted worldwide. Results are encouraging. Lymphocytes that can kill cancer cells are induced and augmented in the patients. This treatment has very mild side effects, as compared to standard chemotherapy regimens. And clinical responses (e.g., tumor regressions) are at least equal if not better than what can be achieved with conventional treatment options. Thus, dendritic cell- based immunotherapy of cancer works in principle. However, it is still far from optimal. Many variables still need to be investigated. One such critical variable will be studied in this project. Langerhans cells are the dendritic cells of the epidermis. There is evidence from many basic research studies that Langerhans cells have some unique properties, such as a better ability to induce killer cells. Here, we attempt to exploit these special features for cancer immunotherapy. The novel aspect of this project is to administer tumor antigens through the skin. They will be applied onto the surface of the skin rather than being injected into the skin, as most previous studies were doing it. Moreover and importantly, tumor antigens will be specifically addressed or targetted to the Langerhans cells in the epidermis by chemically or genetically coupling them to antibodies that find and bind receptor molecules on these Langerhans cells (named DEC-205 and Langerin). It is anticipated that this way of delivery of antigens will elicit stronger immune responses. Experiments addressing these questions will be performed in mouse models, including tumor models as well as with human Langerhans cells. Data from the project will allow us to see how feasible this vaccination strategy will be. It is a promising strategy since it might be applied to all kinds of vaccinations (including those against infectious agents). Moreover, it is simple and less expensive than comparable innovative immunization methods. Data from this project will be translated into eventual clinical studies. They also have the potential to be translated into socio-economic benefits, such as lower treatment costs or even marketable products.