Molecular machines and systems contributing to cancer biology

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

This project is focused on T-cell therapies that take advantage of chimeric antigen receptor (CAR) targeting of a tumor-specific antigen. CAR hinge and transmembrane regions link the antigen recognition domains to the intracellular signal transduction domains. The CAR hinge region has been previously found to contribute to the efficacy of CAR treatment but the required features for optimal design remain elusive. With the long-term goal of contributing to CAR design, we applied structural biology methods to study the structure and dynamic properties of the CD28 CAR hinge (CD28H) that is used in an FDA-approved CD19 CAR for treatment of B-lineage leukemia/lymphoma. We observed local structural elements amidst overall disorder in CD28H. These local structural motifs contribute to an overall loosely formed extended geometry and likely constrain the spacing between the transmembrane and antigen recognition domains. Overall, we developed a pipeline for detecting local and transient structure within intrinsically disordered systems that can be applied generally, and provided fundamental information on CD28H that can inform its future use in CAR T-cell therapies. These findings have also inspired additional experiments to further study how the hinge region affects CAR T-cell:tumor cell interactions by cryo-electron microscopy.