Christian Doppler Laboratory for Next Generation CAR T Cells
T cells engineered to express Chimeric Antigen Receptors (CAR T cells) have shown impressive clinical success for patients with B cell malignancies. However, since CAR T cells are self-replicating living drugs it is difficult to regulate their function after administration to a patient, often resulting in severe side effects such as cytokine release syndrome and neurotoxicity. At the same time, currently used CAR T cells could also potentially attack healthy tissue, since their typical target antigens are always present to some extent on a small fraction of healthy cells. This lack of tumor specificity and the insufficient controllability of CAR T cell function are major hurdles for the clinical implementation of the full potential of CAR T cell therapy until today.
The goal of this “CD Laboratory for Next Generation CAR T cells” is therefore to generate novel molecular tools to minimize the destruction of healthy tissue and to be able to reversibly control CAR T cell activity in the patient.
- The lack of reversible control of CAR T cell activation is addressed by constructing molecular ON-switches that can be controlled by administration of approved, orally available drugs. These novel molecular switches can not only be used to regulate CAR T cell function but will open up a completely new realm of cell engineering.
- The lack of tumor specificity of CAR T cells is addressed by constructing a novel class of AND gate CARs for combinatorial antigen recognition. That is, those CARs are only activated if both antigens A AND B are present on a target cell, but not if only one antigen is expressed. If those two antigens are selected accordingly, this specificity for double-positive cells can greatly improve tumor specificity.
Our CD Laboratory will provide a comprehensive set of novel approaches, in which an essential principle is the use of proteins and small molecules that allow for rapid clinical implementation. Our multidisciplinary approach will enable the generation and clinical translation of novel CAR T cell therapies with improved efficacy, safety and tumor specificity.
F. l. t. r.: Thomas Gabler, Mara Mitstorfer, Charlotte Brey, Manfred Lehner, Magdalena Teufl, Elise Sylvander, Michael Traxlmayr, Benjamin Salzer
New molecular tools for improving safety and specificity of CAR T cell therapy.