Antigen driven cooperation of two single-chain receptors (immunoreceptors) to recognize defined antigen patterns by engineered T cells
Final Report Abstract
Adoptive cell therapy with antigen-specific T cells is currently one of the most effective forms in the immunotherapy of cancer. Patient's T cells are ex vivo engineered with an immunoreceptor (chimeric antigen receptor, CAR) which is composed of one single polypeptide chain, prototypically consistent of an extacellular antibody-derived binding and an intracellular signaling domain derived from CD3ζ and the CD28 costimulatory domain. The project addresses one of the major challenges of the concept, which is to redirect the specific T cell response against tumors while preventing auto-aggression. To solve the situation, we here made use of the fact, that a number of tumors can be distinguished from healthy tissues by a particular pattern of co-expressed „tumor-associated antigens“. Using a thoroughly controlled model system we demonstrate that the T cell discrimination between the two target cells can be achieved by co-expression of two CARs in a specific design to allow full activation only when two antigens are simultaneously targeted. T cells were engineered to co-express two CARs with different specificities, in this example for CEA and ErbB2, and both with different activation domains, i.e., CD3ζ and CD28, respectively. The CARs mediate full T cell activation only when both antigens are simultaneously engaged. We demonstrate increase in specific T cell activation by two co-expressed CARs which functionally co-operate; vice versa, a decreased T cell activation when both CARs could not co-operate due to the molecular CAR design. The feasibility of the concept was demonstrated in an animal model; a productive T cell anti-tumor activation occurred when both target antigens were present on tumor cells while target cells with one antigen only were less or not attacked. The results of this project provide a novel strategy to improve the anti-tumor specificity and avidity of redirected T cells while limiting the risk of auto-reactivity.
