Pre-clinical evaluation of CAR T cells and treatment of solid tumor

The purpose of this study is to evaluate the use of chimeric antigen receptor (CAR) T cells directed against cell surface antigens on solid tumor before this protocol can be tested in the clinic with human patients. We have shown in vitro that CAR T cells efficiently kill tumor cell lines corresponding to the tumor type the CAR is directed against. However, in vivo efficacy of these CAR T cells must be shown in animal studies before Statens Legemiddelverk (SLV) can be requested for the authorization to treat patients in clinical trials. The development of new types of therapy for advanced solid tumors with little treatment alternative and where survival rates are still dismal is an urgent need. CAR T cell therapy has recently been approved by the FDA for treatment of leukaemia and lymphoma due to its recent clinical success in therapy-resistant cancer. For solid tumors there has been much less development and this is our focus. Efficacy testing in vivo is an important part of this development. For this purpose, NOD/SCID (NSG) mice in a solid tumor model system will be treated with CAR Lymphocytes. NSG mice have been chosen since they have no immune system and it is therefore possible to establish human tumors and treat the animals with redirected human lymphocytes. To be able to follow tumor growth without killing the animals we have transformed the tumor cells to express luciferase. This system enables us to take picture of the tumor while the animals are under gas anesthesia using the in vivo imaging system (IVIS), and therefore greatly reduces the number of animals used in each group to 5-10 compared to if we have to sacrifice animals at regular intervals to follow tumors that are not measureable . After the tumors are established, the CAR Lymphocyte cells will be administrated together with IL-2 to increase proliferation and survival of T cells. Tumor growth will be monitored weekly by IVIS. None of these procedures are expected to cause a great deal of discomfort in animals. Tumor cells, lymphocytes and IL-2 will be delivered by syringe. The health condition of the mice will be monitored daily, and animals will be euthanized according to given criteria and tumor load.