Learning the design language of CAR structural components using a high-throughput screening method.

Chimeric antigen receptor (CAR)-T cell therapy is an innovative form of cellular immunotherapy that utilizes T-lymphocytes that are genetically engineered to express a CAR. While initial response rates are often outstanding, the majority of patients suffers from a relapse which is often cause by a lack of sustained effector functionality or persistence of the CAR-T cells. The importance of the CAR architecture to therapeutic outcome is becoming increasingly clear. However, it is unlikely that the full potential of CAR-T-cell therapy will be reached by using a combination of domains derived from only a small subset of immune-related proteins, as is the case today. The main reason behind this limited selection of building blocks is the use of slow and labor-intensive low-throughput methods for the evaluation of novel candidate domains. Only few groups, such as the Birnbaum lab, have developed a high-throughput workflow for the functional evaluation of up to 1 million CAR designs. While those workflows provide invaluable information novel costimulatory domain combinations, it has never been applied to other structural domains of CARs. The aim of this research stay at the Birnbaum lab is to acquire the practical know-how on CAR combinatorial library construction and a high-throughput CAR screening workflow. By applying this knowledge directly under the supervision of the host group, we will attempt to decipher the design language of severely understudied CAR components by screening a sizeable library of potentially valuable CAR domains.

Keywords:CHIMERIC ANTIGEN RECEPTORS

Disciplines:Hematology, Adaptive immunology, Cancer therapy