Cancer is one of the most important challenges medical research has to overcome. Cancer tissue originates from healthy cells mainly through genetic changes that misregulate cellular processes especially growth and metabolism. For this reason the treatment is challenging, as each cancer is different and keeps changing, making it difficult to find the best therapy. Common approaches such as radiation or chemotherapy can lead to severe short and long-term side-effects. To avoid these, the focus of cancer therapy development changed to immunotherapy. Here the ability of the immune system to fight cancer cells is being improved. During the last years, special attention in immunotherapy has been gathered by chimeric antigen receptor (CAR) T cell immunotherapy (Jackson et al., 2016; Fesnak et al., 2016).
In CAR based immunotherapy, T cells are extracted from a patient's blood and genetically modified to express CAR constitutively. T cells, or T lymphocytes, are cells of the immune system which are matured in the thymus and have various functions in fighting pathogens and cancer. The genetically modified T cells are re-injected into the patient where they exhibit an enhanced ability to target cancer cells through the CAR. The CAR is a synthetic receptor composed of signaling subunits of a T-cell receptor and the variable region of an antibody thereby combining the function of antigen binding with T cell activation. As for now, CAR therapies are in clinical trials for B cell lymphomas, two of which were recently approved by the FDA for therapeutic use (Clinical Study CCTL019B2202, Neelapu et al., 2017).
One challenge with CAR T cell immunotherapy is the emergence of a major side effect, the Graft-Versus-Host-Disease (GVHD). The antigen recognized by the CAR is not exclusive for tumor cells. Thus healthy cells presenting the same antigen can be targeted by CAR T cells leading to the damage of healthy tissue (Hartmann et al., 2017; Morgan et al., 2010).
To overcome this issue, we came up with the idea that a locally restricted expression of the CAR would prevent off-target effects. For our project, we designed a genetic logical AND gate which is activated by the tumor microenvironment of solid tumors. Regulated by the AND gate CAR is only expressed if T cells are within tumor tissue. This local restriction of CAR expression should decrease the risk of off-target effects.
Our approach to improve CAR T cell immunotherapy is based on genetic engineering of T cells to express CAR only in the specific tumor microenvironment. This would allow treating cancer patients without impairing the endogenous immunogenicity of the modified T cells, complementing conventional cancer treatments and also minimizing the risk of severe side-effects.